Biological Activities of Some New Secondary Metabolites Isolated from Endophytic Fungi: A Review Study

Abstract

Secondary metabolites isolated from plant endophytic fungi have been getting more and more attention. Some secondary metabolites exhibit high biological activities, hence, they have potential to be used for promising lead compounds in drug discovery. In this review, a total of 134 journal articles (from 2017 to 2019) were reviewed and the chemical structures of 449 new metabolites, including polyketides, terpenoids, steroids and so on, were summarized. Besides, various biological activities and structure-activity relationship of some compounds were aslo described.

1. Introduction

During the growth of microorganisms, some secondary metabolites biologically active are produced to make their lives better. Using chemical and biological methods, Elshafie et al. displayed that the cell-free culture filtrate of Burkholderia gladioli pv. agaricicola (Bga) Yabuuchi has a promising antibacterial activity against the two microorganisms B. megaterium and E. coli [1]. Camele et al. reported that the tested isolate of an endophytic bacterium Bacillus mojavensis showed antagonistic bacterial and fungal activities against several strains as well as biofilm formation ability [2]. Endophytes refer to the microorganisms that exist in various organs, tissues or intercellular space of plants, while the host plants generally do not show any symptoms of infection. Generally speaking, endophytes include endophytic fungi, endophytic bacterium and endophytic actinomycetes [3]. As a very important microbial resource, endophytes exist widely in nature. It is ubiquitous in various terrestrial and aquatic plants. Endophytes have been isolated from bryophytes, ferns, pteridophytes, hornworts, herbaceous plants and various woody plants. The region also ranges from tropical to arctic, from natural wild to agricultural industry ecosystem [4]. They have unique physiological and metabolic mechanisms, which enable them to adapt to the special environment inside plants, and at the same time, they can encode a variety of bioactive substances. In addition, endophytes coevolved with the host plants for a long time to produce some metabolic substances similar or identical to the host plants with medicinal value [5]. Some endophytes can even assist the host of medicinal plants to synthesize effective active compounds, the ground-breaking discovery provides a new method to produce the effective compounds which have similar effects with natural medicines isolated from plant tissues directly. At the same time, it has solved the problem of resource shortage and ecological destruction caused by slow growth of some natural plants and large amount of artificial exploitation [3]. The more beneficial thing is that some of them are environmentally friendly. Elshafie et al. have studied the fungus Trichoderma harzianum strain T22 (Th-T22) and indicated that Th-T22 showed significant mycoremediation ability in diesel-contaminated sand, suggesting that it can be used as a bioremediation agent for diesel spills in polluted sites [6]. Among the common endophytes, the endophytic fungi are most often isolated [4]. The first endophytic fungus was isolated from Perennial ryegrass (Loliumtum eletum) seeds by Vogle in 1898 [7]. Up to now, the study on endophytic fungi has a long history of more than 100 years, but the research on endophytic fungi of medicinal plants has not been formally carried out until the last 30 years, which has gradually attracted the attention of domestic and foreign scholars.

The multiformity of endophytes enable they can produce a variety of secondary metabolites. In recent years, the metabolites isolated from the endophytic fungi include alkaloids, steroids, terpenes, anthraquinones, cyclic peptides, flavonoids commonly [5]. Some secondary metabolites exhibit high biological activities. The antitumor, antibacterial, anti-inflammatory, antiviral, antifungal and other compounds have been produced by different endophytic fungi. Therefore, the chemical variety of secondary metabolites produced by endophytic fungi has advantage for new drug development [8].

In this review, 449 new secondary metabolites, together with their chemical structures and biological activities were summarized. The structure-activity relationships and absolute configureuration of some compounds have also been described. Among all new compounds, terpenoids account for the largest proportion (75%), followed by polyketones (36%). The proportion of different types of compounds in all new compounds is shown in Figure 1. These new compounds were isolated from various fungi associated with different tissues from different plants. As a result, their structures varied a lot, which leads to their multitudinous biological activities. In addition to common antimicrobial activity and anti-tumor activity, some compounds also showed anti-enzyme activity and inhibition of biofilm formation, inhibition of phytoplankton growth, and so on.

2. New Metabolites Isolated from Plant Endophytes 2.1. Terpenoids

2.1.1. Sesquiterpenoids and Their Derivatives

Five new polyketide-terpene hybrid metabolites 1–5 (Figure 2) with highly functionalized groups, were isolated from the endolichenic fungus Pestalotiopsis sp. [9]. Co-cultivation of mangrove endophytic fungus Trichoderma sp. 307 and aquatic pathogenic bacterium Acinetobacter johnsonii B2 led to the production of two new furan-type isoeremophilane sesquiterpenes, microsphaeropsisin B 6 and microsphaeropsisin C 7 (Figure 2). Their absolute configureuration were assigned as 4S, 5R, 7R, 8S, 11S and 4R, 5R, 7R, 8S [10]. Following cultivation on rice medium, a new sesquiterpene, atrichodermone C 8 (Figure 2), was isolated from an endophytic fungal strain named Trichoderma atroviride which was isolated from the bulb of Lycoris radiate [11]. There is an endophytic fungus Pestalotiopsis sp. which was obtained from fruits of Drepanocarpus lunatus (Fabaceae). Co-culture of this fungus with Bacillus subtilis afforded two new sesquiterpenoids pestabacillins A 9 (Figure 2) and pestabacillins B 10 (Figure 2) [12]. Two new sesquiterpene-epoxycyclohexenone conjugates, nectrianolins A 11 (Figure 2) and nectrianolins B 12 (Figure 2), together with a sesquiterpene, nectrianolin C 13 (Figure 2), were isolated from the brown rice culture of Nectria pseudotrichia 120-1NP, an endophytic fungus isolated from Gliricidia sepium. It is of particular interest that 11 and 12 have a rearranged monocyclofarnesyl skeleton (which is uncommon to sesquiterpene-epoxycyclohexane conjugates) instead of a bicyclofarnesyl skeleton which is present in macrophorins, neomacrophorins, myrothecols, and craterellins [13]. It was found that endophytic Nigrospora oryzae stimulated the production of a new tremulane sesquiterpene nigrosirpexin A 14 (Figure 2) from Irpex lacteus [14]. Two novel sesquiterpenoids with an unprecedented tricyclo[4,4,2,1]hendecane scaffold, namely emericellins A 15 (Figure 2) and emericellins B 16 (Figure 2) representing a new skeleton, were isolated from the liquid cultures of an endophytic fungus Emericella sp. XL 029 associated with the leaves of Panax notoginseng [15]. Two trichothecene sesquiterpenoids, trichothecrotocins A 17 (Figure 2) and trichothecrotocins B 18 (Figure 2), and a pair of merosesquiterpenoid racemates, (+)-trichothecrotocin C 19 (Figure 2) and (−)-trichothecrotocin C 20 (Figure 2), were obtained from potato endophytic fungus Trichothecium crotocinigenum by bioguided isolation. Compounds 17 and 18 are trichothecenes possessing new ring systems. Compounds 19 and 20 possess novel 6/6−5/5/5 fused ring system [16]. Chemical investigation on the solid rice culture of Trichoderma atroviride S361, an endophyte isolated from Cephalotaxus fortunei, has afforded a new cyclohexenone sesquiterpenoid, trichodermadione B 21 (Figure 2) [17]. Seven new phenolic bisabolane sesquiterpenoids, (7R,10S)-7,10-epoxysydonic acid 22 (Figure 2), (7S,10S)-7,10-epoxysydonic acid 23 (Figure 2), (7R,11S)-7,12-epoxysydonic acid 24 (Figure 2), (7S,11S)-7,12-epoxysydonic acid 25 (Figure 2), 7-deoxy-7,14-didehydro-12-hydroxysydonic acid 26 (Figure 2), (Z)-7-deoxy-7,8-didehydro-12-hydroxysydonic acid 27 (Figure 2), and (E)-7-deoxy-7,8-didehydro-12-hydroxysydonic acid 28 (Figure 2), were obtained from the culture of an endophytic fungus Aspergillus sp. xy02 isolated from the leaves of a Thai mangrove Xylocarpus moluccensis [18]. Pestalustaines A 29 (Figure 2), one unique sesquiterpene possessing an unusual 5/6/7-fused tricyclic ring system was isolated from the plant-derived Pestalotiopsis adusta [19]. A new acorane sesquiterpene, 3β-hydroxy-β-acorenol 30 (Figure 2), possesses an acorane framework was separated from the extract of the green Chinese onion derived fungus Fusarium proliferatum AF-04 [20]. An examination of the endophytic fungus Trichoderma asperellum A-YMD-9-2 obtained from the marine red alga Gracilaria verrucosa led to the isolation of seven new chromanoid norbisabolane derivatives, trichobisabolins I–L 31–34 (Figure 2) and trichaspsides C–E 35–37 (Figure 2). The discovery of compounds 31–37 greatly diversifies the structures of norbisabolane sesquiterpenes [21]. Oxytropiols A–J 38–47 (Figure 2), ten undescribed highly oxygenated guaiane-type sesquiterpenoids, were isolated from the locoweed endophytic fungus Alternaria oxytropis [22]. Studies on the bioactive extract of mangrove endophytic fungus Pleosporales sp. SK7 led to the isolation of an abscisic acid-type sesquiterpene 48 (Figure 2), named (10S, 2Z)-3-methyl-5-(2,6,6-trimethyl-4-oxocyclohex-2-enyl)pent-2-enoicacid [23]. One new tremulane sesquiterpene, irpexlacte A 49 (Figure 2), was isolated from the endophytic fungus Irpex lacteus DR10-1 waterlogging tolerant plant Distylium chinense [24]. Trichocadinins B−G 50–55 (Figure 2), six new cadinane-type sesquiterpene derivatives, each with C-14 carboxyl functionality, were isolated from the culture extract of Trichoderma virens QA-8, an endophytic fungus obtained from the fresh inner tissue of the medicinal plant Artemisia argyi [25]. Chemical investigation of the EtOAc extract of the plant-associated fungus Alternaria alternate in rice culture led to the isolation of a new sesquiterpene (1R,5R,6R,7R,10S)-1,6-Dihroxyeudesm-4(15)-ene 56 (Figure 2) [26]. An investigation of a co-culture of the Armillaria sp. and endophytic fungus Epicoccum sp. YUD17002 associated with Gastrodia elata led to the isolation of five protoilludane-type sesquiterpenes named epicoterpenes A–E 57–61 (Figure 2). Compound 60 was the first example of an ent-protoilludane sesquiterpenoid scaffold bearing a five-membered lactone. Notably, none of the new compounds were produced by either of the two fungi when cultured alone under the same conditions [27]. A new sesquiterpene lactone, namely colletotrin 62 (Figure 2), was obtained from a rice culture of Colletotrichum gloeosporioides, an endophytic fungus isolated from the stem bark of Cameroonian medicinal plant Trichilia monadelpha (Meliaceae) [28]. Purpurolide A 63 (Figure 2), an unprecedent sesquiterpene lactone with a rarely encountered 5/5/5 spirocyclic skeleton, along with two new 6/4/5/5 tetracyclic sesquiterpene lactones purpurolide B and C 64–65 (Figure 2), were isolated from the cultures of the endophytic fungus Penicillium purpurogenum IMM003 [29]. Bioassay-guided fractionation of the crude extract of fermentation broth of one symbiotic strain Fusarium oxysporum ZZP-R1 derived from coastal plant Rumex madaio Makino, one traditional Chinese medicine used as a treatment of inflammation and toxication, yielded one novel compound, fusariumins D 66 (Figure 2). Chemical structure of 66 was determined as a sesquiterpene ester with a conjugated triene and an unusual oxetene ring by a combination of spectroscopic methods [30].

2.1.2. Diterpenoids

One new cleistanthane-type diterpene zythiostromic acid C 67 (Figure 3), which structure was assigned as 3α,5α,7β,8β-tetrahydroxycleistanth-13(17),15-dien-18-oic acid, was isolated from the brown rice culture of Nectria pseudotrichia 120-1NP [31]. A fungal strain, Drechmeria sp., was isolated from the root of Panax notoginseng. Totally, seven new indole diterpenoids, drechmerins A–G 68–74 (Figure 3), were isolated from the fermentation broth of Drechmeria sp. [32]. A novel 1(2), 2(18)-diseco indole diterpenoid, drechmerin H 75 (Figure 3), was isolated from the fermentation broth of Drechmeria sp. together with a new indole diterpenoid, 2′-epi terpendole A 76 (Figure 3) [33]. An endophytic fungus, Neosartorya fifischeri JS0553, was isolated from G. littoralis plant. From the fungus, a new meroditerpenoid named sartorypyrone E 77 (Figure 3) was isolated [34]. Two new oxoindolo diterpene epimers, anthcolorin G 78 (Figure 3) and anthcolorin H 79 (Figure 3), isolated for the first time from a natural source, were isolated from the solid rice culture of the endophytic fungus Aspergillus versicolor [35]. A new isopimarane derivative which was named as xylaroisopimaranin A 80 (Figure 3) and the absolute configureurations was determined as 4S, 5R, 9R, 10R, 13R and 14S, was isolated from the plant endophytic fungus Xylaralyce sp. (HM-1) [36]. The endolichenic fungus Apiospora montagnei isolated from the lichen Cladonia sp. was cultured on solid rice medium, yielding a new diterpenoid libertellenone L 81 (Figure 3), compound 81 represented the first example of 6,7-seco-libertellenone derivative [37].

2.1.3. Other Terpenoids

Eleven new ophiobolin-type sesterterpenoids, asperophiobolins A−K 82–92 (Figure 4), were isolated from the cultures of the mangrove endophytic fungus Aspergillus sp. ZJ-68. Asperophiobolins A–D (82−85) represented the first examples possessing a five-membered lactam unit between C-5 and C-21 in ophiobolin derivatives. The absolute configureuration of compands were defined as (2S,3R,5S,6R,11R,14R,15S) (82–84), (2S,3R,5S,6R,10S,11R,14R,15S) (85), (2S,6S,10S,11R,14R,15S,18R) (87), (2S,6R,10S,11R,14R,15S,18R) (88), (2S,6S,10S,11R,14R,15S,18S) (89), (2S,6R,10S,11R,14R,15S,18S) (90),(2S,3R,6R,10S,11R,14R,15S,18S) (91), (2R,3R,5R,6R,10S,11R,14R,15S) (92) [38]. From Kadsura angustifolia fermented by an associated symbiotic endophytic fungus, Penicillium sp. SWUKD4.1850, nine undescribed triterpenoids, kadhenrischinins A–H 93–100 (Figure 4), and 7β-schinalactone C 101 (Figure 4) were isolated and established. All these metabolites have been first detected in non-fermented K. angustifolia. Structurally, kadhenrischinins A–D (93–96) belong to the relatively rare class of highly oxygenated schitriterpenoids that contain a unique 3-one-2-oxabicyclo [3,2,1]-octane motif, while kadhenrischinins E–H (97–100) feature acyclopentane ring in a side chain rarely found in the family Schisandraceae [39]. Meroterpenoids with diverse ring systems including five new ones (102–106) (Figure 4), were isolated from Phyllosticta capitalensis, an endophytic fungus from Cephalotaxus fortunei Hook. Compound 102 was the first example with a 9,14-seco ring and a five-membered ring in guignardone derivatives. Compound 103 represented a novel guignardone derivative possessing a 5/7/6/5 ring system with CH2-7 attached to C-4 rather than C-6 in ring D [40]. Nine new meroterpenes, (7R,8R)-8-hydroxysydowic acid 107 (Figure 4), (7S,10S)-10-hydroxy-sydowic acid 108 (Figure 4), (7S,11R)-12-hydroxy-sydowic acid 109 (Figure 4), (7S,11R)-12-acetoxy-sydowic acid 110 (Figure 4), (7R,8R)-1,8-epoxy-11-hydroxy-sydonic acid 111 (Figure 4), 7-deoxy-7,14-didehydro-11-hydroxysydonic acid 112 (Figure 4), 7-deoxy-7,14-didehydro-12-acetoxy-sydonic acid 113 (Figure 4), and (E)-7-deoxy-7,8-didehydro-12-acetoxy-sydonic acid 114 (Figure 4), (7R)-11-hydroxy-sydonic acid methyl ester 115 (Figure 4), were isolated from the solid rice culture of the endophytic fungus Aspergillus versicolor [35]. Bioassay-guided fractionation of the crude extract of fermentation broth of one symbiotic strain Fusarium oxysporum ZZP-R1 derived from coastal plant Rumex madaio Makino, one traditional Chinese medicine used as a treatment of inflammation and toxication, yielded one novel compound, fusariumins C 116 (Figure 4). Chemical structure of 116 was determined as one meroterpene with cyclohexanone moiety [30]. A new monoterpentoid lithocarin D 117, was isolated from the endophytic fungus Diaporthe lithocarpus A740 (Figure 4) [41].

2.2. Ketone Compounds

2.2.1. Polyketides

An endophytic fungus, Eupenicillium sp. LG41, isolated from the Chinese medicinal plant Xanthium sibiricum, was subjected to epigenetic modulation using an NAD⁺-dependent histone deacetylase (HDAC) inhibitor, nicotinamide. Epigenetic stimulation of the endophyte led to enhanced production of two new decalin-derived polyketides with a double bond between C-3 and C-4, eupenicinicols C 118 (Figure 5) and D 119 (Figure 5) [42]. On the basis of One Strain/Many Compounds (OSMAC) strategy, five new polyketides, named phomopsiketones A–C 120–122 (Figure 5), (10S)-10-O-b-D-40-methoxymannopyranosyldiaporthin 123 (Figure 5), and clearanol 124 (Figure 5), were isolated from an endophytic fungus, Phomopsis sp. sh917, harbored in stems of Isodon eriocalyx var. laxiflora [43]. As naturally occurring polyketides, ten new salicyloid derivatives, namely vaccinols J–S 125–134 (Figure 5), were isolated from Pestalotiopsis vaccinii (cgmcc3.9199) endogenous with the mangrove plant Kandelia candel (L.) Druce (Rhizophoraceae) [44]. Twelve new polyketides, penicichrysogenins A–L 135–146 (Figure 5), were isolated from the solid substrate fermentation cultures of a Huperzia serrata endophytic fungus Penicillium chrysogenum MT-12. The structures of 135–139 were established as (2R)-6-hydroxy-2,4-dimethoxy-5-methylphthalide (135), 4,6-dihydroxy-5-hydroxymethylphthalide9 (136), 4,6-dihydroxy-5-methoxymethylphthalide (137), (2R)-4,5-dihydroxy-2,6-dimethoxy-2-pentylphthalide (138), (E)-4,5-dihydroxy-2-(4-hydroxypentylidene)-6-methoxyphthalide(139), respectively [45]. Three new polyketides, cylindrocarpones A–C 147–149 (Figure 5), were isolated from the endophytic fungus, Cylindrocarpon sp., obtained from the tropical plant Sapium ellipticum [46]. Six new xanthone-derived polyketides, named phomoxanthones F–K 150–155 (Figure 5), were isolated from Phomopsis sp. xy21, which was isolated as an endophytic fungus from the Thai mangrove Xylocarpus granatum. Phomoxanthone F 150 represented the first xanthone-derived polyketide containing a 10a-decarboxylated benzopyranone nucleus that was substituted by a 4-methyldihydrofuran-2(3H)-one moiety at C10a. Phomoxanthones G 151 and H 152 are highly oxidized xanthone-derived polyketides containing a novel 5-methyl-6-oxabicyclo [3.2.1] octane motif [47]. Compound 156 (Figure 5), 5,9-dihydroxy-2,4,6,8,10-pentamethyldodeca-2,6,10-trienal, a novel polyketide molecule was isolated from Aspergillus flocculus endophyte isolated from the stem of the medicinal plant Markhamia platycalyx [48]. Three new polyketides, (2S)-2,3-dihydro-5,6-dihydroxy-2-methyl-4H-1-benzopyran-4-one 157 (Figure 5), (2′R)-2-(2′-hydroxypropyl)-4-methoxyl-1,3-benzenediol 158 (Figure 5), and 4-ethyl-3-hydroxy-6-propenyl-2H-pyran-2-one 159 (Figure 5) were isolated from the culture broth of Colletotrichum gloeosporioides, an endophytic fungus derived from the mangrove Ceriops tagal [49]. Five polyketides, paralactonic acids A–E 160–164 (Figure 5) were isolated from Paraconiothyrium sp. SW-B-1, an endophytic fungus isolated from the seaweed, Chondrus ocellatus Holmes [50]. Four new polyketides, alternatains A–D 165–168 (Figure 5), were obtained from the solid substrate fermentation cultures of Alternaria alternata MT-47, an endophytic fungus isolated from the medicinal plant of Huperzia serrata [51]. From extracts of the plant associated fungus Chaetosphaeronema achilleae collected in Iran, two polyketides including a previously unreported isoindolinone named chaetosisoindolinone 169 (Figure 5) and a previously undescribed indanone named chaetosindanone 170 (Figure 5) were isolated [52]. During a survey of the secondary metabolites of endophytic fungi Aspergillus porosus, new polyketides with interesting structural features named porosuphenols A–D 171–174 (Figure 5) were found [53]. Chemical investigation of the EtOAc extract of the plant-associated fungus Alternaria alternate in rice culture led to the isolation of a novel liphatic polyketone, alternin A 175 (Figure 5), which possesses an unprecedented C25 liphatic polyketone skeleton [26]. Five new polyketides, colletotric B 176 (Figure 5), 3-hydroxy-5-methoxy-2,4,6-trimethylbenzoic acid 177 (Figure 5), colletotric C 178 (Figure 5), chaetochromone D 179 (Figure 5) and 8-hydroxy-pregaliellalactone B 180 (Figure 5), were isolated from thmangrove endophytic fungus Phoma sp. SYSU-SK-7 [54]. The EtOAc extract of Phomopsis sp. D15a2a isolated from the plant Alternanthera bettzickiana following fermentation on solid rice medium yielded three new polyketides, phomopones A−C 181–183 (Figure 5) [55]. Three new polyketides including two benzophenone derivatives, penibenzones A (184) and B (185) (Figure 5), and a new phthalide derivative, penibenzone C 186 (Figure 5), were isolated from the solid-substrate cultures of the endophytic fungus Penicillium purpurogenum IMM003 [56].

2.2.2. Other Ketones

A new N-methoxypyridone analog 11S-hydroxy-14-methyl cordypyridone C 187 (Figure 6), was isolated from the co-culture of Hawaiian endophytic fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062 [57]. A novel endophyte Rhytismataceae sp. DAOMC 251461 produced two new dihydropyrones: (R)-4-hydroxy-5-octanoyl-6-oxo-3,6-dihydropyran-2-carboxylic acid (rhytismatone A) 188 (Figure 6) and (R)-methyl-4-hydroxy-5-octanoyl-6-oxo-3,6-dihydropyran-2-carboxylate (rhytismatone B) 189 (Figure 6) [58]. Five new bioactive 2-pyrone metabolites, phomaspyrones A–E 190–194 (Figure 6), were isolated from the culture broth of an endophytic fungus Phomopsis asparagi SWUKJ5.2020 of medicinal plant Kadsura angustifolia. The structures of 190–194 were identified as (S)-5-(1,2-dihydroxyethyl)-6-hydroxymethyl-4-methoxy-2H-pyran-2-one (190),(S)-5-(1-hydroxyethyl)-6-hydroxymethyl-4-methoxy-2H-pyran-2-one (191), (5S,8R)-5,8-dihydroxy-4-methoxy-5,6-dihydropyrano-[3,4-b]pyran-2(8H)-one (192), 4-methoxy-6-methyl-5-(2-oxobutyl)-2H-pyran-2-one (193), 6-(hydroxymethyl)-4-methoxy-5-(2-oxobutyl)-2H-pyran-2-one (194) respectively [59]. Extracts from an endophytic fungus Dendrothyrium variisporum isolated from the roots of the Algerian plant Globularia alypum produced two new minor furanone derivatives: methyl (5S)-5-[(10E,30Z)-hexa-1,3-dienyl]-5-methyl-4-oxo-2-methyl-4,5-dihydrofuran-3 carboxylate ((5S) cis-gregatin B) 195 (Figure 6), (5R)-5-[(10E,30Z)-hexa-1,3-dienyl]-5-methyl-4-oxo-2-[(4S,1E)-4-hydroxypent-1-enyl]-4,5-dihydrofuran-3carboxylate, (graminin D) 196 (Figure 6) [60]. Two new compounds isobenzofuranone A 197 (Figure 6) and indandione B 198 (Figure 6), were isolated from liquid cultures of an endophytic fungus Alternaria sp., which was obtained from the medicinal plant Morinda officinalis. Among them, the indandione 198 showed a rarely occurring indanone skeleton in natural products [61]. An endophytic fungal strain named Trichoderma atroviride was isolated from the bulb of Lycoris radiata. Following cultivation on rice medium, a new cyclopentenone derivative, atrichodermone B 199 (Figure 6), was isolated [11]. One previously undescribed isochromone derivative 6,8-dihydroxy-3-(2-hydroxypropyl)-7-methyl-1H-isochromen-1-one 200 (Figure 6), was isolated from the culture of the endophytic fungus Eurotium chevalieri KUFA 0006 [62]. One previously undescribed pyrone (simplicilopyrone) 201 (Figure 6) was isolated from the endophytic fungus Simplicillium sp. PSU-H41 [63]. Cytosporaphenones A–C, one new polyhydric benzophenone 202 (Figure 6) and two new naphtopyrone derivatives 203–204 (Figure 6), were isolated from Cytospora rhizophorae, an endophytic fungus from Morinda officinalis [64]. A novel pyrone derivative 205 (Figure 6) bearing two fused five-member rings, together with two new naphthalenone derivatives 206–207 (Figure 6), were obtained from the endophytic fungus Fusarium sp. HP-2, which was isolated from “Qi-Nan” agarwood [65]. Two new compounds penibenzophenones A-B 208–209 (Figure 6), were isolated from the EtOAc extract of the endophytic fungus Penicillium citrinum HL-5126 isolated from the mangrove Bruguiera sexangula var. rhynchopetala collected in the South China Sea [66]. Two new isochromanone derivatives, (3S,4S)-3,8-dihydroxy-6-methoxy-3,4,5-trimethylisochroman-1-one 210 (Figure 6) and methyl (S)-8-hydroxy-6-methoxy-5-methyl-4a-(3-oxobutan-2-yl)benzoate 211 (Figure 6), were isolated from the cultures of an endophytic fungus Phoma sp. PF2 obtained from Artemisia princeps [67]. Isoshamixanthone 212 (Figure 6), a new stereoisomeric pyrano xanthone was obtained from the endophytic fungal strain Aspergillus sp. ASCLA isolated from leaf tissues of the medicinal plant Callistemon subulatus [68]. From the endophytic fungus, Cylindrocarpon sp., obtained from the tropical plant Sapium ellipticum, a new pyrone cylindropyrone 213 (Figure 6) was isolated [46]. One new benzophenone derivative, named tenllone I 214 (Figure 6), was isolated from the endophytic fungus Diaporthe lithocarpus A740 [41].

2.3. Alkaloids and Their Derivatives

The endolichenic fungus Apiospora montagnei isolated from the lichen Cladonia sp. was cultured on solid rice medium, yielding a new pyridine alkaloid, 23-O-acetyl-N-hydroxyapiosporamide 215 (Figure 7) [37]. Chaetoindolin A 216 (Figure 7), a new indole alkaloid derivative was isolated from the endophytic fungus Chaetomium globosum CDW7 [69]. A synthetic α,β-unsaturated amide alkaloid (E)-tert-butyl(3-cinnamamidopropyl) carbamate 217 (Figure 7), newly identified as a natural product, was isolated from the EtOAc extract of the endophytic fungus Penicillium citrinum HL-5126 isolated from the mangrove Bruguiera sexangula var. Rhynchopetala [66]. A new alkaloid, 1, 2-dihydrophenopyrrozin 218 (Figure 7), was isolated from an axenic culture of the endophytic fungus, Bionectria sp., obtained from seeds of the tropical plant Raphia taedigera [70]. Two new pyridone alkaloids, cylindrocarpyridones A–B 219–220 (Figure 7), were isolated from the endophytic fungus, Cylindrocarpon sp., obtained from the tropical plant Sapium ellipticum [46]. From Aspergillus versicolor, an endophyte derived from leaves of the Egyptian water hyacinth Eichhornia crassipes (Pontederiaceae), one new compound aflaquinolone H 221 (Figure 7) belonging to dihydroquinolone alkaoids was obtained [71]. Two new spiroketal derivatives as alkaloids with an unprecedented amino group, 2′-aminodechloromaldoxin 222 (Figure 7) and 2′-aminodechlorogeodoxin 223 (Figure 7), were isolated from the plant endophytic fungus Pestalotiopsis flavidula [72]. The biotransformation of lycopodium alkaloid huperzine A (hupA), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. Two previously undescribed compounds 224–225 (Figure 7), were isolated and identified [73]. Chemical investigation of the EtOAc extract of the plant-associated fungus Alternaria alternate in rice culture led to the isolation of a new indole alkaloid 226 (Figure 7) [26]. Bioactivity-guided isolation of the endophytic fungus Fusarium sambucinum TE-6L residing in Nicotiana tabacum L. led to the discovery of two new angularly prenylated indole alkaloids (PIAs) with pyrano[2,3-g]indole moieties, amoenamide C 227 (Figure 7) and sclerotiamide B 228 (Figure 7). Compound 227 containing the 8 bicyclo[2.2.2]diazaoctane core and indoxyl unit was rarely reported [74].

2.4. Penylpropanoids and Their Derivatives

A new isocoumarin (3R,4S,4aR,6R)-4,6,8-trihydroxy-3-methyl-3,4,4a,5,6,7-hexahydroisochromen-1-one 229 (Figure 8) was isolated from an endophyte Mycosphaerellaceae sp. DAOMC 250863 [58]. Using the bioassay-guided method, one new isocoumarin derivative, prochaetoviridin A 230 (Figure 8), was isolated from C. globosum CDW7, an endophyte from Ginkgo biloba [66]. A new isocoumarin derivative pestalotiopisorin B 231 (Figure 8), was isolated from Pestalotiopsis sp. HHL-101, an endophytic fungus obtained from Chinese mangrove plant Rhizophora stylosa [75]. In continuing search of fungal strain Nectria pseudotrichia 120-1NP, two new isocoumarins, namely, nectriapyrones A 232 (Figure 8) and B 233 (Figure 8) were identified [31]. Two new isocoumarin dimers 234–235 (Figure 8) were isolated from Aspergillus versicolor, an endophyte derived from leaves of the Egyptian water hyacinth Eichhornia crassipes (Pontederiaceae) [71]. Pestalustaines 236 (Figure 8), one unprecedented coumarin derivative bearing 6/6/5/5-fused tetracyclic ring system, was isolated from a plant-derived endophytic fungus Pestalotiopsis adusta [19]. Compounds 237 (Figure 8) and 238 (Figure 8), determined as two novel isocoumarin derivatives with a different butanetriol group at C-3, were produced by T. harzianum (Trichoderma harzianum) Fes1712 isolated from Rubber Tree Ficus elastica leaves [76]. Two pairs of new isocoumarin derivatives penicoffrazins B and C, 239–240 (Figure 8), were isolated from Penicillium coffeae MA-314, an endophytic fungus obtained from the fresh inner tissue of the leaf of marine mangrove plant Laguncularia racemosa [77]. A new dihydroisocoumarin, diaporone A 241 (Figure 8), was isolated from the ethyl acetate extract of the cultures of the endophytic fungus Diaporthe sp. [78].

2.5. Lactones

From the seeds of the traditional medicinal plant Ziziphus jujuba growing in Uzbekistan, the fungal endophyte Alternaria sp. was isolated. Extracts of this fungus yielded a new natural phthalide derivative 7-methoxyphthalide-3-acetic acid 242 (Figure 9) [79]. Three new lactone Derivatives isoaigialones, A, B, and C 243–245 (Figure 9), were isolated from the crude EtOAc extract of a Phaeoacremonium sp., an endophytic fungus obtained from the leaves of Senna spectabilis. 245 is epimeric at C-7 relative to compound 244 [80]. A new phytotoxic bicyclic lactone (3aS,6aR)-4,5-dimethyl-3,3a,6,6a-tetrahydro-2H-cyclopenta [b]furan-2-one 246 (Figure 9), was isolated from the ethyl acetate extract of fermentation broth of Xylaria curta 92092022 [81]. Three new lactones de-O-methyllasiodiplodins, (3R,7R)-7-hydroxy-de-O-methyllasiodiplodin 247 (Figure 9) and (3R)-5-oxo-deO-methyllasiodiplodin 248 (Figure 9), together with (3R)-7-oxo-de-O-methyllasiodiplodin 249 (Figure 9) were isolated from the co-cultivation of mangrove endophytic fungus Trichoderma sp. 307 and aquatic pathogenic bacterium Acinetobacter johnsonii B2 [10]. Two new lactones, pestalotiolactones A 250 (Figure 9) and B 251 (Figure 9), were isolated from the axenic culture of the endophytic fungus Pestalotiopsis sp., obtained from fruits of Drepanocarpus lunatus (Fabaceae) [12]. Active metabolites investigation of Talaromyces sp. (strain no. MH551540) associated with Xanthoparmelia angustiphylla afforded a new 3-methoxy-4,8-bihydroxymethyl-6-methyl-2,4,6-3en-δ-lactone, talaromycin A 252 (Figure 9) [82]. Introducing an alien carbamoyltransferase (asm21) gene into the Streptomyces sp. CS by conjugal transfer, as a result, one recombinatorial mutant named CS/asm21-4 was successfully constructed. From the extracts of the CS/asm21-4 cultured on oatmeal solid medium, a new macrolide hookerolide 253 (Figure 9) was obtained [83]. Four new aromatic butenolides, asperimides A–D 254–257 (Figure 9), were isolated from solid cultures of a tropical endophytic fungus Aspergillus terreus. Compounds 254–257 represent the first examples of butenolides with a maleimide core isolated from Aspergillus sp. [84]. In ongoing search for bioactive metabolites from the genus of Aspergillus, four new butenolides, namely terrusnolides A–D 258–261 (Figure 9) were isolated from an endophytic Aspergillus from Tripterygium wilfordii. Compound 258 was a butenolide derived by a triple decarboxylation. Furthermore, compounds 259–261 were the 4-benzyl-3-phenyl-5H-furan-2-one derivatives with an isopentene group fused to the benzene ring [85]. Chemical investigation on the culture extract of H. fuscum fermented on rice led to the isolation of one new 10-membered lactone 5,6-Epoxy-phomol 262 (Figure 9) [86]. Three new spirocyclic anhydride derivatives 263–265 (Figure 9) were isolated from the endophytic fungus Talaromyces purpurogenus obtained from fresh leaves of the toxic medicinal plant Tylophora ovate [87]. A new δ-lactone penicoffeazine A, 266 (Figure 9) was isolated from Penicillium coffeae MA-314, an endophytic fungus obtained from the fresh inner tissue of the leaf of marine mangrove plant Laguncularia racemosa [77]. On the basis of One Strain/Many Compounds (OSMAC) strategy, a new natural product 267 (Figure 9), was isolated from an endophytic fungus, Phomopsis sp. sh917, harbored in stems of Isodon eriocalyx var. laxiflora [43]. A chemical investigation on metabolites of Phyllosticta sp. J13-2-12Y isolated from the leaves of Acorus tatarinowii was carried out, which led to the isolation of four new phenylisotertronic acids, R-xenofuranone B 268 (Figure 9), S-xenofuranone B 269 (Figure 9), enantio-flflavipesin B 270 (Figure 9), and S-3-hydroxy-4,5-diphenylfuran-2(5H)-one 271 (Figure 9) [88]. An endophytic fungus Pestalotiopsis microspora isolated from the fruits of Manilkara zapota was cultured in potato dextrose broth media. Chromatographic separation of the EtOAc extract of the broth and mycelium led to the isolation of a new azaphilonoid named pitholide E 272 (Figure 9) [89].

2.6. Anthraquinones

An endophytic fungus Penicillium citrinum Salicorn 46 isolated from Salicornia herbacea Torr., Produced one new citrinin derivative, pencitrinol 273 (Figure 10) [90]. Lachnum cf. pygmaeum DAOMC 250335 was obtained from ascospores originating from a collection of apothecia occurring on a dead P. rubens twig, from this strain, a new chlorinated para-quinone, chloromycorrhizinone A 274 (Figure 10) was isolated [58]. The endolichenic fungus Apiospora montagnei isolated from the lichen Cladonia sp. was cultured on solid rice medium, yielding a new xanthone derivative 8-hydroxy-3-hydroxymethyl-9-oxo-9Hxanthene-1-carboxylic acid methyl ether 275 (Figure 10) [37]. One previously undescribed metabolite anthraquinone derivative acetylquestinol 276 (Figure 10), was isolated from the culture of the endophytic fungus Eurotium chevalieri KUFA 0006 [62]. New pulvilloric acid-type azaphilones 277–280 (Figure 10) were produced by Nigrospora oryzae co-cultured with Irpex lacteus [14]. A new shunt product spiciferone F 281 (Figure 10) together with two new analogs spiciferones G 282 (Figure 10) and H 283 (Figure 10) were isolated from endophytic fungus Phoma betae inhabiting in plant Kalidium foliatum (Pall.) [91]. Bioassay-guided fractionation of the dichloromethane extract of the fungus Neofusicoccum austral SYSU-SKS024 led to the isolation of three new ethylnaphthoquinone derivatives, neofusnaphthoquinone A 284 (Figure 10), 6-(1-methoxylethy1)-2,7-dimethoxyjuglone 285 (Figure 10), (3R,4R)-3-methoxyl-botryosphaerone D 286 (Figure 10), Neofusnaphthoquinone A 285 is the third example of the unsymmetrical naphthoquinone [92]. The EtOAc extract of strain Nectria pseudotrichia 120-1NP led to the identification of one new naphthoquinone, namely, nectriaquinone B 287 (Figure 10) [31]. Cytoskyrin C 288 (Figure 10), a new bisanthraquinone with asymmetrically cytoskyrin type skeleton, was isolated from an endophytic fungus ARL-09 (Diaporthe sp.) from Anoectochilus roxburghii [93]. Three new naphthomycins O–Q 289–291 (Figure 10), were obtained from the solid cultured medium of recombinatorial mutant strain CS/asm21-4 (By introducing an alien carbamoyltransferase (asm21) gene into the strain Streptomyces sp. CS (CS) by conjugal transfer) [83]. From the fermentation broth of the endophytic fungus Xylaria sp.SYPF 8246, one new compound, xylarianins B 292 (Figure 10) was isolated [94]. An undescribed substituted dihydroxanthene-1,9-dione, named funiculosone 293 (Figure 10), was isolated together from the culture filtrates of Talaromyces funiculosus (Thom) Samson, Yilmaz, Frisvad & Seifert (Trichocomaceae), an endolichenic fungus isolated from lichen thallus of Diorygma hieroglyphicum (Pers.) Staiger & Kalb (Graphidaceae), in India [95]. One new dihydroxanthenone derivative globosuxanthone E 294 (Figure 10) was obtained from the crude extracts of two endophytic fungi Simplicillium lanosoniveum (J.F.H. Beyma) Zare & W. Gams (Sarocladium strictum) PSU-H168 and PSU-H261 which were isolated from the leaves of Hevea brasiliensis [96]. Two new naphthoquinone derivatives, 6-hydroxy-astropaquinone B 295 (Figure 10) and astropaquinone D 296 (Figure 10) were isolated from Fusarium napiforme, an endophytic fungus isolated from the mangrove plant, Rhizophora mucronata [97].

2.7. Sterides

Two new steroids, (24R)-22, 23-dihydroxy-ergosta-4,6,8(14)-trien-3-one 23-β-d-glucopyranoside 297 (Figure 11), and xylarester 298 (Figure 11), were isolated from the extract of endophytic Xylaria sp. solid culture. Compound 298 has an unprecedent ergosta skeleton with a six-membered lactonic group in A ring [98]. An endophytic fungus, Chaetomium sp. M453 isolated from Huperzia serrata (Thunb. ex Murray) Trev yield four new steroids including three unusual C25 steroids, neocyclocitrinols E–G 299–301 (Figure 11), and 3β-hydroxy-5,9-epoxy-(22E,24R)-ergosta-7,22-dien-6-one 302 (Figure 11) [99]. Three new methylated Δ8-pregnene steroids, stemphylisteroids A–C 303–305 (Figure 11) were isolated from the medicinal plant Polyalthia laui-derived fungus Stemphylium sp.AZGP4-2. The discovery of those three steroids is a further addition to diverse and complex array of methylated steroids [100]. Three new ergosterol derivatives, namely, fusaristerols B [(22E,24R)-3-palmitoyl-19(10→6)-abeo-ergosta-5,7,9,22-tetraen-3β-ol] 306 (Figure 11), fusaristerols C [(22E,24R)-ergosta-7,22-diene-3β,6β,9α-triol] 307 (Figure 11), and fusaristerols D [(22E,24R)-ergosta-7,22-diene-3β,5α,6β,9α-tetraol 6-acetate] 308 (Figure 11), were isolated and characterized from the endophytic fungus Fusarium sp. isolated from Mentha longifolia L. (Labiatae) roots growing in Saudi Arabia [101]. A new ergosterol derivative, 23R-hydroxy-(20Z,24R)-ergosta-4,6,8(14),20(22)-tetraen-3-one 309 (Figure 11), was isolated from the co-culture between endophytic fungus Pleosporales sp. F46 and endophytic bacterium Bacillus wiedmannii Com1 both inhibiting in the medicinal plant Mahonia fortunei. This is the first example of isolation of a ergosterol derivative with a Δ20(22)-double bond in the side chain [102]. Two new sterol derivatives, namely ergosterimide B 310 (Figure 11) and demethylincisterol A5 311 (Figure 11), were isolated from the rice fermentation culture of Aspergillustubingensis YP-2 [103].

2.8. Other Types of Compounds

An endophytic fungus Talaromyces stipitatus SK-4 was isolated from the leaves of a mangrove plant Acanthus ilicifolius. Its crude extract exhibited significant antibacterial activity was purified to afford two new depsidones, talaromyones A and B 312–313 (Figure 12) [104]. Four new amide derivatives, designated as cordycepiamides A–D 314–317 (Figure 12), were isolated from the EtOAc-soluble fraction of the 95% EtOH extract of long-grain rice fermented with the endophytic fungus C. ninchukispora BCRC 31900, derived from the seeds of medicinal plant Beilschmiedia erythrophloia Hayata [105]. One new 4-hydroxycinnamic acid derivatives, methyl 2-{(E)-2-[4-(formyloxy)phenyl]ethenyl}-4-methyl-3-oxopentanoate 318 (Figure 12), was isolated from an EtOAc extract derived from a solid rice medium of endophytic fungal strain Pyronema sp. (A2-1 & D1-2) [106]. When endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla cultured in the absence of the epigenetic modifier, it can produced a new metabolite, (S,Z)-5-(3′,4-dihydroxybutyldiene)-3-propylfuran-2(5H)-one 319 (Figure 12) [107]. One new citrinin derivatives, pencitrin 320 (Figure 12) was isolated from an endophytic fungus P. citrinum 46 derived from Salicornia herbacea Torr by adding CuCl₂ into fermentation medium [90]. Two new cytosporone derivatives 321–322 (Figure 12) were isolated from the endophytic fungus Phomopsis sp. PSU-H188 [108]. Extensive chemical investigation of the endophytic fungus, Fusarium solani JK10, harbored in the root of the Ghanaian medicinal plant Chlorophora regia, using the OSMAC (One Strain Many Compounds) approach resulted in the isolation of seven new 7–desmethyl fusarin C derivatives 323–329 (Figure 12) [109]. A new biphenyl derivative 5,5′-dimethoxybiphenyl-2,2′-diol 330 (Figure 12), was isolated from the mangrove endophytic fungus Phomopsis longicolla HL-2232 [110]. A new hexanedioic acid analogue, (2S,5R)-2-ethyl-5-methylhexanedioic acid 331 (Figure 12), was isolated from Penicillium sp. OC-4, an endophytic fungus associated with Orchidantha chinensis [111]. The endophytic fungus Curvularia sp. strain (M12) was isolated from a leaf of the medicinal plant Murraya koenigii and cultured on rice medium. Chromatographic analysis led to the isolation of four new compounds, murranofuran A 332 (Figure 12), murranolide A 333 (Figure 12), murranopyrone 334 (Figure 12), and murranoic acid A 335 (Figure 12) [112]. The cultivation of the mangrove-derived fungus Rhytidhysteron rufulum AS21B in acidic condition could change its secondary metabolite profile. Investigation of the culture broth extract led to the isolation and identification of two new spirobisnaphthalenes 336–337 (Figure 12) [113]. On the basis of One Strain/Many Compounds (OSMAC) strategy, one new natural product 338 (Figure 12), was isolated from an endophytic fungus, Phomopsis sp. sh917, harbored in stems of Isodon eriocalyx var. laxiflora [43]. Extracts from an endophytic fungus Dendrothyrium variisporum isolated from the roots of the Algerian plant Globularia alypum yielded three new anthranilic acid derivatives 339–341 (Figure 12) [60]. An endophytic fungal strain named Trichoderma atroviride was isolated from the bulb of Lycoris radiata. Following cultivation on rice medium, a novel 3-amino-5-hydroxy-5-vinyl-2-cyclopenten-1-one dimer, atricho dermone A 342 (Figure 12), was isolated. Compound 342 is the first example of cyclopentene dimer [11]. A new chaetoglobosin, penochalasin K 343 (Figure 12) bearing an unusual six-cyclic 6/5/6/5/6/13 fused ring system, was isolated from the solid culture of the mangrove endophytic fungus Penicillium chrysogenum V11 [114]. Three previously undescribed metabolites, including two prenylated indole 3-carbaldehyde derivatives 344–345 (Figure 12), an anthranilic acid derivative 346 (Figure 12) were isolated from the culture of the endophytic fungus Eurotium chevalieri KUFA 0006. The structures of compounds were established as 2-(2-methyl-3-en-2-yl)-1H-indole-3-carbaldehyde (344), (2,2-dimethylcyclopropyl)-1H-indole-3-carbaldehyde (345), 2[(2,2-dimethylbut-3-enoyl)amino]benzoic acid (346) [62]. Nine previously undescribed depsidones simplicildones A–I 347–355 (Figure 12) were isolated from the endophytic fungus Simplicillium sp. PSU-H41 [63]. Six new compounds including four tyrosine derivatives terezine M 356 and phomarosines A–C 357–359 (Figure 12), and two new hydantoin derivatives, (S)-5-isopropyl-3-methoxyimidazolidine-2,4-dione 360 (Figure 12) and (S)-5-(4-hydroxybenzoyl)-3-isobutyrylimidazolidine-2,4-dione 361 (Figure 12), were obtained from the investigation of the endophytic fungus Phoma herbarum PSU-H256, which was isolated from a leaf of Hevea brasiliensis [115]. New mellein derivative; 4-methylmellein 362 (Figure 12) was isolated from the ethyl acetate extract of the endophytic fungus Penicillium sp. isolated from the leaf of Senecio flavus (Asteraceae) [116]. One novel cytochalasin, named jammosporin A 363 (Figure 12) was isolated from the culture of the endophytic fungus R. sanctae-cruciana, harboured from the leaves of the medicinal plant A. lebbeck [117]. An endophytic fungus Arthrinium arundinis TE-3 was isolated and purified from the fresh leaves of cultivated tobacco (Nicotiana tabacum L.). Chemical investigation on this fungal strain afforded three new prenylated diphenyl ethers 364–366 (Figure 12) [118]. A novel indene derivative 367 (Figure 12), have been purified from an ethyl acetate extract of the plant-associated fungus Aspergillus flavipes Y-62, isolated from Suaeda glauca (Bunge) Bunge [119]. The endophytic fungus Mycosphaerella sp. (UFMGCB2032) was isolated from the healthy leaves of Eugenia bimarginata, a plant from the Brazilian savanna. Two novel usnic acid derivatives, mycousfuranine 368 (Figure 12) and mycousnicdiol 369 (Figure 12), were isolated from the ethyl acetate extract [120]. Intriguingly, incorporaion of Cu²⁺ into the PDB medium of the endophytic fungus, Anteaglonium sp. FL0768 enhanced production of metabolites and drastically affected the biosynthetic pathway resulting in the production of pentaketide dimers, palmarumycin CE4 370 (Figure 12). The structure of palmarumycin CE4 370 was established as (2β,4aα,5β,8β,8aα)-2,3,4a,5,8,8a-hexahydro-5-hydroxy-spiro [2,8-epoxynaphthalene]-1(4H)-2′-naphtho[1,8-de][1,3]dioxin-4-one [121]. Three new compounds, including rotational isomers 371–372 (Figure 12) and 373 (Figure 12) were isolated from the solid cultures of the endophytic fungus Penicillium janthinellum SYPF 7899, compound 372 is the rotamer of 371 [122]. The chemical assessment of endophyte Phaeophleospora vochysiae sp. nov from Vochysia divergens, revealed a new compound 3-(sec-butyl)-6-ethyl-4,5-dihydroxy-2-methoxy-6-methylcyclohex-2-enone 374 (Figure 12) [123]. Co-cultivation of fungus Bionectria sp. either with Bacillus subtilis or with Streptomyces lividans resulted in the production of two new o-aminobenzoic acid derivatives, bionectriamines A and B 375–376 (Figure 12) [70]. Chemical investigation on the solid rice culture of Trichoderma atroviride S361, an endophyte isolated from Cephalotaxus fortunei, has afforded a pair of novel N-furanone amide enantiomers, (−)-trichodermadione A 377 (Figure 12) and (+)-trichodermadione A 378 (Figure 12). The structure of 377 was identified as (4′R,2E)-N-(2-ethyl-5-methyl-3-oxo-2,3-dihydrofuran-2-yl)-5-hydroxy-3-methylpent-2-enamide [17]. Secondary metabolites were isolated from the fermentation broth of the endophytic fungus Xylaria sp.SYPF 8246, including four new compounds, xylarianins A–D 379–382 (Figure 12), three new natural products, 6-methox-ycarbonyl-2′-methyl-3,5,4′,6′-tetramethoxy-diphenyl ether 383 (Figure 12), 2-chlor-6-methoxycarbonyl-2′-rnethyl-3,5,4′,6′-tetramethoxy-diphenyl ether 384 (Figure 12), and 2-chlor-4′-hydroxy-6-methoxy carbonyl-2′-methyl-3,5,6′-trimethoxy-diphenyl ether 385 (Figure 12) [94]. Bysspectin A 386 (Figure 12), a polyketide-derived octaketide dimer with a novel carbon skeleton, and two new precursor derivatives, bysspectins B and C 387–388 (Figure 12), were obtained from an organic extract of the endophytic fungus Byssochlamys spectabilis that had been isolated from a leaf tissue of the traditional Chinese medicinal plant Edgeworthia chrysantha [124]. Fusarithioamide B 389 (Figure 12), a new aminobenzamide derivative with unprecedented carbon skeleton was separated from Fusarium chlamydosporium EtOAc extract isolated from Anvillea garcinii (Burm.f.) DC. Leaves (Asteraceae) [125]. The study of endophytic fungus Annulohypoxylon stygium (Xylariaceae family) isolated from Bostrychia radicans algae led to the isolation of a novel compound, 3-benzylidene-2-methylhexahydropyrrolo [1,2-α] pyrazine-1,4-dione 390 (Figure 12) [126]. A new 2H-benzindazole derivative, alterindazolin A 391 (Figure 12), has been isolated from cultures of the endophyte Alternaria alternata Shm-1obtained from the fresh wild body of Phellinus igniarius. The structure of 391 was elucidated for N-benzyl-3-[p-hydroxy phenyloxygen]-benz[e]indazole [127]. One new pentenoic acid derivative, named 1,1′-dioxine-2,2′-dipropionic acid 392 (Figure 12) and a new natural product, named 2-methylacetate-3,5,6-trimethylpyrazine 393 (Figure 12), were obtained from the Cladosporium sp. JS1-2, an endophytic fungus isolated from the mangrove Ceriops tagal collected in South China Sea [128]. Chemical assessment of the new species Diaporthe vochysiae sp. nov. (LGMF1583), isolated as endophyte of the medicinal plant Vochysia divergens, revealed two new carboxamides, vochysiamides A 394 (Figure 12) and B 395 (Figure 12) [129]. Two new eremophilane derivatives lithocarins B 396 (Figure 12) and 397 (Figure 12), were isolated from the endophytic fungus Diaporthe lithocarpus A740 [41]. Five new cytochalasans 398–402 (Figure 12) were isolated from the rice fermentation of fungus Xylaria longipes isolated from the sample collected at Ailao Moutain [130]. A new compound which was determined as 10-Ethylidene-2,4,9-trimethoxy-10,10a-dihydro-7,11-dioxa-benzo[b]heptalene-6,12-dione 403 (Figure 12) was isolated from Penicillium citrinum inhabiting Parmotrema sp. [131]. Investigation of the culture broth of Periconia macrospinosa KT3863 led to discover two new chlorinated melleins (3R,4S)-5-chloro-4-hydroxy-6-methoxymellein 404 (Figure 12), (R)-7-chloro-6-methoxy-8-O-methylmellein 405 (Figure 12) [132]. Two new compounds, lasdiplactone 406 (Figure 12) and lasdiploic acid 407 (Figure 12) were isolated from the chloroform extract of cell free filtrate of the endophytic fungus Lasiosdiplodia pseudotheobromae. The structure of 406 was characterized as (3S,4S,5R)–4–hydroxymethyl–3,5–dimethyldihydro–2–furanone [133]. Studies on the bioactive extract of mangrove endophytic fungus Pleosporales sp. SK7 led to the isolation of one new asterric acid derivative named methyl 2-(2-carboxy-4-hydroxy-6-methoxylphenoxy)-6-hydroxy-4-methyl-benzoate 408 (Figure 12) [23]. Chemical investigation of the mangrove-derived fungus Aspergillus sp. AV-2 following fermentation on solid rice medium led to the isolation of a new phenyl pyridazine derivative 409 (Figure 12) and a new prenylated benzaldehyde derivative, dioxoauroglaucin 410 (Figure 12) [134]. Three new furan derivatives, irpexlacte B–D 411–413 (Figure 12), were isolated from the endophytic fungus Irpex lacteus DR10-1 waterlogging tolerant plant Distylium chinense. Structures of compounds 411–413 were established as 5-(2α-hydroxypentyl) furan-2-carbaldehyde, 5-(1α-hydroxypentyl) furan-2-carbaldehyde, 5-(5-(2-hydroxypropanoyl) furan-2-yl) pentan-2-one, respectively [24]. Four new alkyl aromatics, penixylarins A–D 414–417 (Figure 12), were isolated from a mixed culture of the Antarctic deep-sea-derived fungus Penicillium crustosum PRB-2 and the mangrove-derived fungus Xylaria sp. HDN13-249. UPLC-MS data and an analysis of structural features showed that compounds 414 and 415 were produced by collaboration of the two fungi, while compounds 416–417 could be produced by Xylaria sp. HDN13-249 alone, but noticeably increased quantities by co-cultivation [135]. The co-culture of marine red algal-derived endophytic fungi Aspergillus terreus EN-539 and Paecilomyces lilacinus EN-531 induced the production of a new terrein derivative, namely asperterrein 418 (Figure 12) [136]. Fractionation and purification of the ethyl acetate extract of Diaporthe lithocarpus, an endophytic fungus from the leaves of Artocarpus heterophyllus, yielded one new compound, diaporthindoic acid 419 (Figure 12) [137]. A new diketopiperazine cyclo-(L-Phe-N-ethyl-L-Glu) 420 (Figure 12), was isolated from the cultures of an endophytic fungus Aspergillus aculeatus F027 [138]. Four novel compounds with g-methylidene-spirobutanolide core, fusaspirols A–D 421–424 (Figure 12), were isolated from the brown rice culture of Fusarium solani B-18. Compound 422 was found as the regioisomer of 421 [139]. One new polyacetylene glycoside 425 (Figure 12), one new brasilane-type sesquiterpenoid glycoside 426 (Figure 12), and two novel isobenzofuran-1(3H)-one derivatives 427–428 (Figure 12) were isolated from the solid culture of the endolichenic fungus Hypoxylon fuscu [86]. Chemical investigation of the crude extracts of both endophytic fungi Simplicillium lanosoniveum (J.F.H. Beyma) Zare & W. Gams PSU-H168 and PSU-H261 resulted in the isolation of three new compounds including two depsidones, simplicildones J and K 429–430 (Figure 12) and one dihydroxanthenone derivative, globosuxanthone E 431 (Figure 12) [96]. The apple juice supplemented solid rice media led to significant changes in the secondary metabolism of the endophytic fungus, Clonostachys rosea B5-2, and induced the production of four new compounds, (−)-dihydrovertinolide 432 (Figure 12), and clonostach acids A 433 (Figure 12), B 434 (Figure 12), and C 435 (Figure 12) [140]. Six new nonadride derivatives 436–441 (Figure 12) were isolated from the endophytic fungus Talaromyces purpurogenus obtained from fresh leaves of the toxic medicinal plant Tylophora ovate [87]. One new cyclic tetrapeptide, 18-hydroxydihydrotentoxin 442 (Figure 12), and a new amide, 6-hydroxyenamidin 443 (Figure 12) were obtained from the endophytic fungus Phomopsis sp. D15a2a isolated from the plant Alternanthera bettzickiana [55]. From an endophytic microorganism, Aureobasidium pullulans AJF1, harbored in the flowers of Aconitum carmichaeli, two unique lipid type new compounds (3R,5R)-3-(((3R,5R)-3,5-dihydroxydecanoyl)oxy)-5-hydroxydecanoic acid 444 (Figure 12), and (3R,5R)-3-(((3R,5R)-5-(((3R,5R)-3,5-dihydroxydecanoyl)oxy)-3-hydroxydecanoyl)oxy)-5-hydroxydecanoic acid 445 (Figure 12) were obtained [141]. The fungal strain Alternaria alternata JS0515 was isolated from Vitex rotundifolia (beach vitex). From the gungus one new altenusin derivative 446 (Figure 12), was isolated [142]. An investigation of a co-culture of the Armillaria sp. and endophytic fungus Epicoccum sp. YUD17002 associated with Gastrodia elata led to the isolation three aryl esters 447–449 (Figure 12) [27].

3. Biological Activity 3.1. Antimicrobial Activity

3.1.1. Antifungal Activity

New polyketide-terpene hybrid metabolites 1 and 5 were tested for their inhibition activity following the NCCLS recommendations against six phytopathogenic fungi Botrytis cinerea (ACCC 37347), Verticillium dahliae (ACCC 36916), Fusarium oxysporum (ACCC 37438), Alternaria solani (ACCC 36023), Fusarium gramineum (ACCC 36249), and Rhizoctonia solani (ACCC36124) obtained from Agricultural Culture Collection of China (ACCC). The antifungal assay displayed that 1 and 5 exhibited pronounced biological effects against F. oxysporum with MIC (minimum inhibitory concentration) value of 8 g/mL, whereas 5 can potently inhibited F. gramineum at concentration of 8 g/mL, compared with the positive control ketoconazole (MIC value of 8 g/mL) [9].

Compounds 15–16 were evaluated for antifungal activities against six fungal strains, including Rhizoctonia solani, Verticillium dahliae Kleb, Helminthosporium maydis, Fusarium oxysporum, Botryosphaeria berengeriana and Colletotrichum acutatum Simmonds. Both compounds displayed moderate activities against three fungal strains Verticillium dahliae Kleb, Helminthosporium maydis, and Botryosphaeria dothidea with MIC values of 25–50 μg/mL [15].

The inhibitory activities of compounds 17–20 against four phytopathogenic fungi, including Phytophthora infestane (late blight), Alternaria solani (early blight), Rhizoctonia solani (black scurf), Fusarium oxysporum (blast), were evaluated. Compounds 17–20 all showed potent inhibitory activities toward A. solani and F. oxysporum with MIC value of 16 μg/mL, 32 μg/mL, 8 μg/mL, 8 μg/mL and 32 μg/mL, 16 μg/mL, 16 μg/mL, 16 μg/mL, respectively, while 19–20 weakly inhibited P. infestans and R. solani with MIC value of 128 μg/mL, 64 μg/mL and 128 μg/mL, 32 μg/mL, respectively. Hygromycin B was used as Positive control (MIC values of P. infestans, A. solani, R. solani, and F. oxysporum were 8 μg/mL, <4 μg/mL, 8 μg/mL, 64 μg/mL, respectively) [16].

Antifungal activity of compounds 50–55 against 14 plant-pathogenic fungi Alternaria solani QDAU-14 (AS), Bipolaris sorokiniana QDAU-7 (BS), Ceratobasidium cornigerum QDAU-8 (CC), C. gloeosporioides Penz QDAU-9 (CG), Fusarium graminearum QDAU-10 (FG), F. oxysporum f. sp. cucumebrium QDAU-16 (FOC), F. oxysporum f. sp. momordicae QDAU-17 (FOM), F. oxysporum f. sp. radicis lycopersici QDAU-5 (FOR), F. solani QDAU-15 (FS), Glomerella cingulate QDAU-2 (GC), Helminthosporium maydis QDAU-18 (HM), Penicillium digitatum QDAU-11 (PD), P. piricola Nose QDAU-12 (PP), and Valsa mali QDAU-13 (VM) were carried out by the microplate assay. Compound 50 exhibited inhibitory activity against the 13 test fungi with MIC values of 4 μg/mL (AS), 1 μg/mL (BS), 16 μg/mL (CC), 8 μg/mL (CG), 8 μg/mL (FG), 1 μg/mL (FOC), 2 μg/mL (FOM), 64 μg/mL (FOR), 4 μg/mL (FS), 1 μg/mL (GC), 8 μg/mL (PD), 4 μg/mL (PP), 16 μg/mL (VM), respectively, while compounds 50–55 showed activity against Fusarium oxysporum f. sp. cucumebrium with MIC values ranging from 1 to 64 μg/mL. 51 exhibited inhibitory activity against the 6 test fungi with MIC values of 32 μg/mL (AS), 8 μg/mL (BS), 32 μg/mL (FS), 4 μg/mL (GC), 8 μg/mL (PD), 4 μg/mL (PP), respectively. 52 exhibited inhibitory activity against the 4 test fungi with MIC values of 64 μg/mL (FOR), 1 μg/mL (GC), 8 μg/mL (PP), 32 μg/mL (VM), respectively. 53 exhibited inhibitory activity against the 3 test fungi with MIC values of 64 μg/mL (FOR), 16 μg/mL (PD), 1 μg/mL (PP), respectively. 54 exhibited inhibitory activity against Helminthosporium maydis with MIC value of 16 μg/mL. 55 exhibited inhibitory activity against P. piricola Nose with MIC values of 4 μg/mL (AS). Amphotericin B was used as the positive control against fungi with MIC values of 2 μg/mL (AS), 0.5 μg/mL (BS), 8 μg/mL (CC), 0.5 μg/mL (CG), 2 μg/mL (FG), 0.5 μg/mL (FOC), 1 μg/mL (FOM), 2 μg/mL (FOR), 4 μg/mL (FS), 0.5 μg/mL (GC), 2 μg/mL(HM), 2 μg/mL (PD), 2 μg/mL (PP), 8 μg/mL (VM), respectively [25].

Compounds 68–74 were assayed for their antifungal activities against C. albicans. Geneticin (G418), was used as positive control with the MIC value of 6.3 μg/mL. Compound 69 displayed inhibitory effect against C. albicans with an MIC value of 12.5 μg/mL, while compounds 68 and 74 exhibited weak inhibitory effect against C. albicans with MIC values of 100 μg/mL and 150 μg/mL [32].

Antifungal activities (Minimum inhibitory concentrations; MICs) of the isolated metabolite 170 were determined using a serial dilution assay against Mucor hiemalis DSM 2656. Compound 170 showed moderate to weak antifungal activity against Mucor hiemalis DSM 2656 with a MIC value of 33.33 μg/mL [52].

One fungus Candida albicans (ATCC 10231) was used for antifungal tests, the results showed that compound 177 exhibited significant antifungal activity against C. albicans with the MIC value of 2.62 μg/mL. The positive control for antifungal tests was used by ketoconazole with MIC value of 0.10 μg/mL [54].

The methylated dihydropyrone 189 and compound 274 were tested for in vitro antifungal activity using the Oxford diffusion assay against M. violaceum (Microbotryum violaceum) and S. cerevisiae (Saccharomyces cerevisiae), 189 and 274 exhibited moderate antifungal activity, inhibiting the growth of S. cerevisiae and M. violaceum at 25 μg/mL. Nystatin was the positive control for antifungal assays, previous studies had shown the MIC values of nystatin in the S. cerevisiae culture used was 4 µg/mL and for M. violaceum was 2 µg/mL [58].

Minimum Inhibitory Concentration (MIC) assays were used to assess antifungal activity of the compounds against anti-phytopathogenic activity against seven pathogenic fungi Alternaria alternata (Aa), Botrytis cinerea (Bc), Cochliobolus heterostrophus (Ch), Colletotrichum lagenarium (Cl), Fusarium oxysporum (Fo), Gaeumannomyces graminis (Gg), and Thielaviopsis basicola (Tb). Compound 227 showed potent and specific activity against 4 fungi with MIC values of 32 μg/mL(Bc), 16 μg/mL(Ch), 8 μg/mL(Fo), 8 μg/mL(Tb), respectively, whereas compound 228 showed moderate activity against 3 fungi with MIC values of 16 μg/mL(Bc), 32 μg/mL(Ch), 32 μg/mL(Fo) respectively. Prochloraz, a commercialized broad-156 spectrum fungicide widely used in agriculture, was used as positive antifungal control with MIC values of 8 μg/mL(Bc), 16 μg/mL(Ch), 8 μg/mL(Fo), 8 μg/mL(Tb), respectively. To the best of our knowledge, this is the first study to show that PIAs exhibit inhibitory activity against plant-pathogenic fungi [74].

Prochaetoviridin A 230 was evaluated for its antifungal activities against 5 pathogenic fungi S. sclerotiorum, B. cinerea, F. graminearum, P. capsici and F. moniliforme at the concentration of 20 µg/mL. It showed moderate antifungal activity with inhibition rates ranging from 13.7% to 39.0% [69].

Compounds 244 and 245 were evaluated against phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum (Cladosporium sphaerospermum) using direct bioautography. The results showed that 244 exhibited antifungal activity, with a detection limit of 5 μg, for both fungi, while compound 245 displayed weak activity (detection limit > 5 μg), with a detection limit of 25 μg. Nystatin was used as a positive control, showing a detection limit of 1 μg [80].

Compound 266 was tested for antimicrobial activities against two plant-pathogenic fungi Fusarium oxysporum f. sp. momordicae nov. f. and Colletotrichum gloeosporioides, and exhibited potent activity against both strains with MIC values of 5 µM, which was close to that of the positive control, amphotericin B (MIC = 0.5 µM) [77].

Compounds 289–291 were assayed for antifungal activity against phytopathogenic fungi M. grisea and F. verticillioides, they showed evident inhibition of phytopathogenic fungi. The MIC values of compounds 289–291 were 200 μg/mL, 50 μg/mL and 50 μg/mL against M. Grisea and 200 μg/mL, 100 μg/mL and 100 μg/mL against F. verticillioides. Hygromycin B was the positive control against fungus with the MIC values of 50 μg/mL against both M. Grisea and F. verticillioides [83].

The purified metabolite 293 was tested for antimicrobial activity against selected pathogens namely C. albicans. Funiculosone (293) displayed antimicrobial activity inhibiting fungal pathogens. Funiculosone was able to inhibit the growth of C. albicans with an IC₅₀ (50% inhibitory concentration) of 35 μg/mL [95].

Antifungal activity was determined against C. neoformans ATCC90113. The results showed that globosuxanthone E 294 displayed antifungal activity against Cryptococcus neoformans ATCC90113 with the MIC value of 32 μg/mL. Amphotericin B was used as a positive control for antifungal activity and exhibited an MIC value of 0.5 μg/mL [96].

The new compound, penochalasin K 343 was tested for its antifungal activity against four phytopathogenic fungi including C. musae, C. gloeosporioides, P. italicm, and R. solani. Compound 343 displayed excellent selective activities against the two phytopathogenic fungi Colletotrichum gloeosporioides (Penz) Sacc. (C. gloeosporioides), and Rhizoctonia solani Kühn (R. solani), with MIC values of 6.13 µM and 12.26 µM, respectively. Moreover, the activity towards C. gloeosporioides and R. solani were about ten-fold and two-fold better than those of the positive control carbendazim, respectively. Whereas only moderate or weak inhibitory activities were exhibited by compound 343 towards Colletotrichum musae (Berk. and M. A. Curtis) Arx. (C. musae) and Penicillium italicum Wehme (P. italicm). Carbendazim and the solvent were adopted as positive and negative control, respectively. The MIC values of Carbendazim against C. gloeosporioides, R. solani, C. musae and P. italicm were 65.38 µM, 32.69 µM, 32.69 µM and 16.34 µM [114].

The isolated compound 349 was evaluated for antifungal activities against C. neoformans and P. marneffei, it displayed weak antifungal activity against C. neoformans with MIC value of 32 μg/mL. Amphotericin B was used as positive control for fungi, displayed the MIC values of 1.0 μg/mL and 2.0 μg/mL against C. neoformans and P. marneffei [63].

Three fungi (Aspergillus flavus, Fusarium oxysporum and Candida albicans) were used in antifungal activity tests by disk diffusion method, the antifungal activity was recorded as clear zones of inhibition surrounding the disc (mm). Compound 362 showed antifungal activity against F. oxysporum (zone of inhibition was 6 mm) and variable activities against A. flavus and the yeast C. albicans (zone of inhibition was 5 mm). Nystatin (10 mg/disc) was used as standard antifungal (zone of inhibition against A. flavus and F. oxysporum were 12 mm and 17 mm) [116].

The antifungal activity against six commonly occurring plant-pathogenic fungi Alternaria alternata, Cochliobolus heterostrophus, Gaeumannomyces graminis, Glomerella cingulata, Mucor hiemalis, and Thielaviopsis basicola of compounds 364–365 were evaluated. Compounds 364 and 365 showed selective antifungal activity against Mucor hiemalis with minimum inhibitory concentration (MIC) values of 8 µg/mL and 4 µg/mL, respectively. Prochloraz was used as positive control with MIC value of 8 µg/mL against Mucor hiemalis [118].

In search for novel antifungal compounds, 368 and 369 were tested against C. neoformans and C. gattii. Compounds 368 and 369 exhibited moderate antifungal activities against Cryptococcus neoformans and Cryptococcus gattii, each with minimum inhibitory concentration values of 50.0 μg/mL and 250.0 μg/mL, respectively [120].

The antifungal activity of the compound 374 were evaluated against fungal strains Phyllosticta citricarpa LGMF06 and Colletotrichum abscissum LGMF1268 in order to select the best culture conditions to produce bioactive secondary metabolites. The isolated compound 374 displayed antifungal activity against the citrus phytopathogen Phyllosticta citricarpa with the inhibition zone of 30 mm. Amphotericin B was used as positive control with the inhibition zone of 37 mm [123].

The antifungal effect of 389 was assessed by agar disc diffusion assay towards Candida albicans (AUMC No. 418), Geotrichium candidum (AUMC No. 226), and Trichophyton rubrum (AUMC No. 1804) as fungi. It exhibited selective antifungal activity towards C. albicans (MIC 1.9 µg/mL and IZD 14.5 mm), comparing to the antifungal standard clotrimazole (MIC 2.8 µg/mL and IZD 17.9 mm), whilst, it had moderate activity against G. candidum (MIC 6.9 µg/mL and IZD 28.9 mm) [125].

Compound 418 was tested for antimicrobial activities against five plant-pathogenic fungi A. brassicae, Colletotrichum gloeosprioides, Fusarium oxysporum, Gaeumannomyces graminis, and P. piricola. It exhibited inhibitory activity against A. brassicae and P. piricola with the same MIC value of 64 µg/mL. The positive control against A. brassicae and P. piricola was amphotericin B with MIC values of 4 µg/mL and 8 µg/mL respectively [136].

Antifungal activity was determined against C. neoformans ATCC90113. Simplicildone K 430 and globosuxanthone E 431 displayed weak antifungal activity against Cryptococcus neoformans ATCC90113 with the same MIC values of 32 μg/mL. Amphotericin B was used as a positive control for antifungal activity and exhibited an MIC value of 0.5 μg/mL against C. neoformans ATCC90113 [96].

3.1.2. Antibacterial Activity

The new compound 9 was evaluated for its antibacterial activities against Mycobacterium tuberculosis, Staphylococcus aureus (ATCC25923), S. aureus (ATCC700699), Enterococcus faecalis (ATCC29212), E. faecalis (ATCC51299), E. faecium (ATCC35667), E. faecium (ATCC700221) and Acinetobacter baumannii (ATCCBAA1605). It showed very weak inhibitory effect against M. tuberculosis (MIC > 50 µM) [12].

Compounds 15–16 were also evaluated for their antibacterial activity against twelve bacteria strains, including Micrococcus lysodeikticus, Bacillus subtilis, Bacillus cereus, Micrococcus luteus, Staphyloccocus aureus, Bacillus megaterium, Bacterium paratyphosum B, Proteusbacillm vulgaris, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter aerogenes. Compounds 15–16 displayed moderate activities against three bacterial strains (Bacillus subtilis, Bacillus cereus and Escherichia coli) with MIC values of 25–50 μg/mL [15].

Compounds 23–24, 26 and 28 were evaluated for their antimicrobial activities against the Gram-positive strains Staphylococcus aureus ATCC 25923 and Mycobacterium smegmatis ATCC 607, Gram-negative strains Escherichia coli ATCC 8739 and Pseudomonas aeruginosa ATCC 9027, by the liquid growth inhibition in 96-well microplates. Compounds 23–24, 26 and 28 displayed mild antibacterial activities against the Gram positive strain Staphylococcus aureus ATCC 25923 with IC₅₀ values ranging from 31.5 to 41.9 µM [18].

New compounds 49, 411–413 were evaluated for antibacterial activity against P. aeruginosa (CMCC(B)10,104). Compared with the positive control (Gentamicin, 0.18 µM), compounds 49, 411–413 showed moderate activity with MIC values of 24.1 µM, 32.3 µM, 35.5 µM and 23.8 µM respectively [24].

Antimicrobial evaluation against one human pathogen Escherichia coli EMBLC-1 (EC), 10 marine-derived quatic bacteria Aeromonas hydrophilia QDIO-1 (AH), Edwardsiella tarda QDIO-2 (ET), E. ictarda QDIO-10, Micrococcus luteus QDIO-3 (ML), Pseudomonas aeruginosa QDIO-4 (PA), Vibrio alginolyticus QDIO-5, V. anguillarum QDIO-6 (VAn), V. harveyi QDIO-7 (VH), V. parahemolyticus QDIO-8 (VP), and V. vulnificus QDIO-9 (VV), was carried out by the microplate assay. Compound 50 showed activity with the same MIC value of 8 µg/mL against 4 bacteria ((EC) (AH) (PA) and (VH)) and the value of 4 µg/mL against V. parahemolyticus. Compound 51 showed activity with the MIC values of 16 µg/mL (EC), 8 µg/mL (PA) and 16 µg/mL (VH). Compound 52 showed activity with the MIC values of 8 µg/mL (EC), 8 µg/mL (AH), 4 µg/mL (PA), 2 µg/mL (VH) and 8 µg/mL (VP). While compound 55 had activity against aquatic pathogens Edwardsiella tarda and Vibrio anguillarum with MIC values of 1 μg/mL and 2 μg/mL, respectively, comparable to that of the positive control chloramphenicol (2 µg/mL (EC), 4 µg/mL (AH), 0.5 µg/mL (ET), 4 µg/mL (ML), 2 µg/mL (PA), 1 µg/mL (VAn), 1 µg/mL (VH), 4 µg/mL (VP), 1 µg/mL (VV)) [25].

Compounds 66 and 116 were evaluated for their antimicrobial activities against three human pathogenic strains (Escherichia coli ATCC 25922, Staphyloccocus aureus ATCC 25923 and Candida albicans ATCC 10231) by microbroth dilution method in 96-well culture plates. Bioassay results indicated that compound 116 displayed potent activity against Staphyloccocus aureus with an MIC value of 6.25 µM, which was equal to that of ampicillin sodium as a positive control, and compound 66 had a moderate inhibitory effect on S. aureus with an MIC value of 25.0 µM [30].

Compounds 70 and 74 were assayed for their antimicrobial activities against S. aureus, B. cereus, B. subtillis, P. aeruginosa, and K. pneumonia. The results showed that compounds 70 and 74 displayed weak antimicrobial effects with the same MIC value of 100 µg/mL against B. subtillis and S. aureus. Ampicillin was used as positive control with MIC values of 8 µg/mL and 3.5 µg/mL against S. aureus and B. subtillis [32].

Compound 119 was evaluated for antibacterial activities in vitro against Gram-Positive and Gram-Negative Bacteria (Staphylococcus aureus (DSM 799), Escherichia coli (DSM 1116), Escherichia coli (DSM 682), Bacillus subtilis (DSM 1088) and Acinetobacter sp. (DSM 586)). It was active against Staphylococcus aureus with an MIC value of 0.1 μg/mL. Streptomycin and Gentamicin were used as references against Staphylococcus aureus with MIC values of 5.0 μg/mL and 1.0 μg/mL, respectively. Comparison of 119 with 118 (>10.0 µg/mL against Staphylococcus aureus) and confirmed that the substitution at C-11 plays an important role in increasing the antibacterial activity against the selected bacterium [42].

The antibacterial activity of 157 and 159 was evaluated against five pathogenic bacteria of Micrococcus tetragenus, Staphylococcus aureus, Streptomyces albus, Bacillus cereus, and Bacillus subtilis. Compound 157 showed potent antimicrobial activity against B. cereus with the MIC value of 12.5 µg/mL, Compound 159 also showed potent antimicrobial activities against B. subtilis, S. aureus, and S. albus with the same MICs value of 12.5 µg/mL. Ciprofloxacin was used as a positive control with MIC values of 6.15 µg/mL, 5.60 µg/mL, 0.20 µg/mL, 1.50 µg/mL and 6.15 µg/mL against M. tetragenus, B. cereus, B. subtilis, S. aureus and S. albus [49].

The antimicrobial activity was determined by the paper disk diffusion method (100 μg compound in 8 mm paper disk), using meat peptone agar for Staphylococcus aureus and Pseudomonas aeruginosa, peptone yeast agar for Candida albicans, and potato dextrose agar for Aspergillus clavatus. 164 showed moderate antibacterial activity against Staphylococcus aureus NBRC 13276 (5: 24 mm) at a concentration of 100 μg/disk (MIC value: 3.2 μg/mL). Chloramphenicol was used for positive control against S. aureus (1 μg/mL) [50].

Antimicrobial activities (Minimum inhibitory concentrations; MICs) of the isolated metabolite 170 was determined using a serial dilution assay against Bacillus subtilis DSM 10, Chromobacterium violaceum DSM 30191, Escherichia coli DSM 1116, Micrococcus luteus DSM 1790, Pseudomonas aeruginosa DSM PA14, Staphylococcus aureus DSM 346, and Mycobacterium smegmatis DSM ATCC700084. Compound 170 showed moderate antibacterial activity against Staphylococcus aureus DSM 346 and Bacillus subtilis DSM 10, respectively, with a MIC value of 33.33 μg/mL. Oxytetracyclin was used as positive control with MIC values of 0.2 μg/mL and 4.16 μg/mL against Staphylococcus aureus DSM 346 and Bacillus subtilis DSM 10, respectively [52].

Antimicrobial tests were used for the disc diffusion method. Two Gram-positive methicillin-resistent Staphylococcus aureus, Bacillus subtilis (ATCC 6633), two Gram-negative pseudomonas aeruginosa (ATCC 9027), Salmonella typhimurium (ATCC 6539), were used. Compound 176 showed strong antibacterial activity against the P. aeruginosa and MRSA with the MIC values of 1.67 µg/mL and 3.36µg/mL, respectively. Compound 177 exhibited significant antibacterial activity against B. subtilis with the MIC value of 5.25 µg/mL. Positive control for antifungal tests were used by Ampicillin with the MIC values of 0.15 µg/mL, 0.15 µg/mL and 0.07 µg/mL against P. aeruginosa, MRSA (Methicillin-resistant Staphylococcus aureus) and B. subtilis, respetively. The results indicated that the methylester displayed improved biological activity and showed a selective antibacterial activity against P. aeruginosa and MRSA. Compound 176 exhibited more strong antimicrobial activity than compound 177 [54].

Antibacterial activity was determined against five pathogenic bacteria Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 11778), Staphyloccocus epidermidis (ATCC 12228) and Staphylococcus albus (ATCC 8799) by the microplate assay method. Compound 208 showed weak antibacterial activity against Staphylococcus aureus with a MIC value of 20 μg/mL. Ciprofloxacin was used as the positive control [66].

Antimicrobial activity testing of the compound 212 was carried out against a set of microorganisms using paper-disk diffusion assay. 212 exerted moderate-high activities (13 mm, 16 mm, 15 mm, 10 mm, 11 mm and 14 mm) against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Saccharomyces cerevisiae, Bacillus cereus and Bacillus subtilis ATCC 6633. Gentamycin was used as positive control with the diameter of agar diffusion of 22 mm, 18 mm, 17 mm, 23 mm, 20 mm and 18 mm against the 5 bacteria as mentioned above [68].

Minimum Inhibitory Concentration (MIC) assays were used to assess antibacterial activity of the isolated compounds 227–228 against human pathogens (Escherichia coli, Micrococcus luteus, and Pseudomonas aeruginosa) and plant pathogen (Ralstonia solanacearum). Chloromycetin was used as a positive antibacterial control. Notably, compound 227 demonstrated potent activity against P. aeruginosa with an MIC value of 1 μg/mL, which was better than that of the positive control chloromycetin (MIC = 4 μg/mL). Compound 228 displayed activity against Micrococcus luteus and Pseudomonas aeruginosa with the same MIC value of 8 μg/mL (2 μg/mL and 4 μg/mL against Micrococcus luteus and Pseudomonas aeruginosa for Chloromycetin). In contrary to compounds 228 and the known compound A (Figure 13), B (Figure 13) showed stronger antibacterial activity (MIC values of 4, 4, 8, and 8 μg/mL against E. coli, M. luteus, P. aeruginosa, and R. solanacearum, respectively), indicating that hydroxylation at C-10 can augment antibacterial activity [74].

Compound 229 was tested for in vitro antimicrobial activity against 2 bacteria B. subtilis (ATCC 23857), and E. coli (ATCC 67878). Chloramphenicol was the antibacterial positive control. 229 showed modest antibiotic activity to E. coli with an MIC value of 100 µg/mL [58].

Antimicrobial activities were determined against four terrestrial pathogenic bacteria, including Pseudomonas aeruginosa, Methicillinresistant Staphylococcus aureus, Bacillus subtilis and Escherichia coli by the microplate assay method. Compound 231 exhibited modest antibacterial activity against Escherichia coli and Pseudomonas aeruginosa with 12.5 µg/mL, 50 µg/mL, respectively [75].

Antimicrobial activity was estimated by the inhibitory zone to five indicator microorganisms (Bacillus subtilis CMCC 63501, Candida albicans CMCC 98001, Escherichia coli CMCC 44102, Pseudomonas aeruginosa CMCC 10104 and Staphylococcus aureus CMCC 26003). Compounds 237 and 238 exhibited growth inhibitory activity against E. coli with MIC values of 32 µg/mL. Chloramphenicol was used as positive control with an MIC value of 4 µg/mL against E. coli [76].

Compound 241 was tested for antibacterial activity against Bacillus subtilis (ATCC 6633), Staphylococcus aureus (CGMCC 1.2465), Streptococcus pneumoniae (CGMCC 1.1692), Escherichia coli (CGMCC 1.2340), the results showed that 241 displayed modest antibacterial activity against B. subtilis with MIC value of 66.7 µM (the positive control gentamycin showed MIC value of 1.3 µM) [78].

Compound 246 was evaluated by the agar diffusion method against Gram-positive and Gram-negative bacteria, 246 showed moderate antibacterial activity against both Pseudomonas aeruginosa ATCC 15442 (13 mm) and Staphylococcus aureus NBRC 13276 (13 mm), respectively, at a concentration of 100 μg/disk [81].

Compounds 253, 289–291 were assayed for their antibacterial activities against Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium. All of the four compounds exhibited antibacterial activities against Escherichia coli, Salmonella typhimurium, and Staphylococcus aureus with the same MIC values of 25 µg/mL, 50 µg/mL and 25 µg/mL, respectively. Ampicillin was the positive control against bacteria, the MIC of ampicillin was lower than 0.78 μg/mL against Salmonella typhimurium, and Staphylococcus aureus, while the MIC value against Escherichia coli was 100 µg/mL [83].

The antimicrobial activity was determined by the paper disk diffusion method (100 μg compound in 8 mm paper disk), using meat peptone agar for Staphylococcus aureus and Pseudomonas aeruginosa. Comound 287 exhibited antibacterial activity against S. aureus and P. aeruginosa with MIC values (μg/mL) of >50 and 6.25. Chloramphenicol and kanamycin were used for positive control against S. aureus and P. aeruginosa (each 1 μg/mL), respectively [31].

Compound 293 was tested for antimicrobial activity against selected pathogens namely S. aureus, E. coli and Pseudomonas aeruginosa C. Gessard. Funiculosone (293) displayed antimicrobial activity inhibiting the bacterial pathogens. Funiculosone was able to inhibit the growth of E. coli, S. aureus and C. albicans with IC₅₀ of 25 μg/mL and 58 μg/mL and 35 μg/mL respectively [95].

Compounds 295–296 were evaluated for antimicrobial activity against Gram-positive and Gram-negative bacteria. Compounds 295 and 296 showed moderate antibacterial activity against S. aureus NBRC 13276 and P. aeruginosa ATCC 15442 (MIC values of 6.3 µg/mL and 12.5 µg/mL for S. aureus NBRC 13276, 6.3 µg/mL and 6.3 µg/mL for P. aeruginosa ATCC 15442) [97].

Compounds 303–304 were evaluated for their antibacterial activities against six pathogenic bacteria including M. tetragenus, S. aureus, S. albus, B. cereus, B. subtilis, E. coli. Compound 303 showed antibacterial activity against E. coli with the MIC value of 6.25 μg/mL, and 304 exhibited a broad spectrum of antibacterial activities against six pathogenic with the MIC value ranging from 12.5 to 50 μg/mL (MIC values: 50 µg/mL for M. tetragenus, 25 µg/mL for S. aureus, >50 µg/mL for S. albus, 25 µg/mL for B. cereus, 12.5 µg/mL for B. subtilis and 50 µg/mL for E. coli). Ciprofloxacin was used as a positive control (MIC values: 0.313 µg/mL for M. tetragenus and S. aureus, 0.625 µg/mL for S. albus, B. cereus, B. subtilis and E. coli) [100].

The antibacterial activities of pure compound 309 was evaluated against Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis and Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli using the disk diffusion assay. The new compound 309 showed inhibitory activity against S. aureus at 0.04 µg/paper disk, and the diameter of inhibition zone was 0.71 cm. The MIC for compound 309 against S. aureus was 100 µg/mL using the broth microdilution method, while streptomycin was employed as the positive control with an MIC of around 50 µg/mL [102].

Two Gram-positive bacteria Bacillus subtilis (ATCC6633) and Staphylococcus aureus ATCC (25923) were used. The antibacterial assay and the determination of the minimum inhibitory concentration (MIC) were determined according to continuous dilution method in the 96-well plates. Compound 313 showed antibacterial activity against Bacillus subtilis with an MIC value of 12.5 μg/mL. Ciprofloxacin was the positive control [104].

Compound 318 was tested for antibacterial activity against Mycobacterium marinum ATCCBAA-535. Although rifampin as positive control showed significantly in vitro antibacterial activity against Mycobacterium marinum ATCCBAA-535 with IC₅₀ of 2.1 µM, compound 318 also exhibited potential inhibitory activity with IC₅₀ of 64 µM [106].

The antibacterial activities of the isolated compounds 325–329 were evaluated against the soil bacterium Acinetobacter sp. BD4 (Gram–negative), the environmental strain of Escherichia coli (Gram–negative), as well as human pathogenic strains of Staphylococcus aureus (Gram–positive) and Bacillus subtilis (Gram–positive). The standard references employed were streptomycin (MIC values: 1.0 µg/mL against Escherichia coli, 10.0 µg/mL against Acinetobacter sp. BD4) and gentamicin (MIC values: 1.0 µg/mL against Escherichia coli, 5.0 µg/mL against Acinetobacter sp. BD4). Compounds 325–326 and 328, demonstrated pronounced activity at 10.0 μg/mL against the soil bacterium Acinetobacter sp. BD4 comparable to streptomycin. Compounds 327 and 329 displayed antibacterial efficacies against Escherichia coli with the same MIC value of 5.0 µg/mL [109].

Antibacterial activity of the new compound 330 against Vibrio parahaemolyticus and Vibrio anguillarum was determined by the conventional broth dilution assay. 330 showed moderate inhibitory effects on Vibrio parahaemolyticus with an MIC value of 10 μg/mL. Ciprofloxacin was used as a positive control [110].

Antibacterial efficacies of the metabolite 339 were determined by serial dilution assay. Compound 339 showed strong activity against Bacillus subtilis and Micrococcus luteus with MIC values of 8.33 µg/mL and 16.66 µg/mL, respectively, while the MIC values of Oxytetracyclin used as the positive control against Bacillus subtilis and Micrococcus luteus were 4.16 µg/mL and 0.40 µg/mL, respectively. While the MIC value of compound C (Figure 13) against Mucor hiemalis (16.66 µg/mL) was the same as that of nystatin used as positive control. The two active metabolites are anthranilic acid derivatives with a phenylethyl core. Since metabolite 340, which contains a phenylmethyl group instead of a phenylethyl residue, was not active, it was concluded that the phenylethyl moiety in compounds 339 and C is essential for their antimicrobial activity [60].

The isolated compound 347, which was obtained in sufficient amounts, was evaluated for antimicrobial activities against S. aureus ATCC25923 and methicillin-resistant S. aureus. Simplicildone A 347 displayed weak antibacterial against Staphylococcus aureus with MIC value of 32 µg/mL. Vancomycin which was used as positive control for bacteria, displayed the MIC values of 0.5 µg/mL and 1.0 µg/mL against both S. aureus and methicillin-resistant S. aureus [63].

The antimicrobial activity of compound 367 was evaluated using the strains of methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli. Compound 367 exhibited weaker activity in comparison to the positive control tetracycline against methicillin-resistant S. aureus (MRSA) with the MIC value of 128 µg/mL, and against K. pneumoniae and P. aeruginosa with equal MIC values of 32 µg/mL [119].

Compounds 371–373 were assayed for their antimicrobial activities against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli. Compounds 371–372 exhibited significant inhibitory activities against B. subtilis and S. aureus with MIC values of 15 µg/mL and 18 µg/mL, respectively. Compound 373 showed moderate inhibitory activities against B. subtilis (MIC 35 µg/mL) and S. aureus (MIC 39 µg/mL). Ampicillin (MIC values: 8 µg/mL, 3.5 µg/mL, 10 µg/mL, 10 µg/mL and 2.5 µg/mL against the 5 bacteria mentioned above) and kanamycin (MIC values: 4 µg/mL, 1.0 µg/mL, 8 µg/mL, 9 µg/mL and 4 µg/mL against the 5 bacteria mentioned above) served as the positive control. In addition, morphological observation showed the rod-shaped cells of B. subtilis growing into long filaments, which reached 1.5- to 2-fold of the length of the original cells after treatment with compounds 371–372. The coccoid cells of S. aureus exhibited a similar response and swelled to a 2-fold volume after treatment with compounds 371–372 [122].

The antimicrobial activity of the compound 374 was evaluated against the Gram-positive bacteria Staphylococcus aureus (ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA) (BACHC-MRSA). The resulting inhibition zones were measured in millimeters. 374 displayed antibacterial activity against sensitive and resistant S. aureus, the diameter of inhibition zone was 14 mm, Ampicillin was antibacterial control with the diameter of inhibition zone of 30 mm [123].

Compounds 388 was tested for its antimicrobial activities against Escherichia coli ATCC 25922, Staphyloccocus aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228, and Mycobacterium Smegmatis MC 2155 ATCC70084. Compound 388 was active against Escherichia coli ATCC 25922 and Staphyloccocus aureus ATCC 25923 with MIC values of 32 µg/mL and 64 µg/mL, respectively. Levofloxacin was used as a positive control with MIC value of 0.12 µg/mL [124].

Fusarithioamide B 389 has been assessed for antibacterial activities towards various microbial strains (Staphylococcus aureus (AUMC No. B-54) and Bacillus cereus (AUMC No. B-5) as Gram-positive bacteria, Escherichia coli (AUMC No. B-53), Pseudomonas aeurginosa (AUMC No. B-73), and Serratia marscescens (AUMC No. B-55) as Gram-negative bacteria) by disc diffusion assay. It possessed high antibacterial potential towards E. coli (Inhibition zone diameter (IZD): 25.1 ± 0.60 mm, MIC value: 3.7 ± 0.08 µg/mL), B. cereus (Inhibition zone diameter (IZD): 23.0 ± 0.36 mm, MIC value: 2.5 ± 0.09 µg/mL), and S. aureus (Inhibition zone diameter (IZD): 17.4 ± 0.09 mm, MIC value: 3.1 ± 0.11 µg/mL) compared to ciprofloxacin used as antibacterial standard (Inhibition zone diameter (IZD): 15.3 ± 0.07 mm, MIC value: 3.4 ± 0.32 µg/mL for S. aureus, Inhibition zone diameter (IZD): 21.2 ± 0.51 mm, MIC value: 2.9 ± 0.20 µg/mL for B. cereus, Inhibition zone diameter (IZD): 25.6 ± 0.22 mm, MIC value: 3.9 ± 0.06 µg/mL for E. coli) [125].

The new compounds were evaluated for their antibacterial activities against five terrestrial pathogenic bacteria, including S. aureus (ATCC 27154), Staphylococcus albus (ATCC 8799), B. cereus (ATCC 11778), Escherichia coli (ATCC 25922), and Micrococcus luteus (ATCC 10240) by the microplate assay method. The result showed that Compounds 392–393 showed moderate antibacterial activities against Staphylococcus aureus with the MIC values of 25.0 µg/mL and 12.5 µg/mL, respectively. Ciprofloxacin was used as positive control with the MIC value of 0.39 µg/mL [128].

The MIC of compound 395 against Staphylococcus aureus (MSSA), Methicillin resistant Staphylococcus aureus (MRSA) and Klebsiella pneumoniae carbapenemase-producing (KPC) was performed. Vochysiamide B 395 displayed considerable antibacterial activity against the Gram-negative bacterium Klebsiella pneumoniae (KPC), a producer of carbapenemases, MIC of 80 μg/mL in comparison with positive controls meropenem and gentamicin with MIC values of 45 μg/mL and 410 μg/mL against KPC [129].

The antimicrobial activities of compounds were tested against six microorganisms by the microdilution method, including Mycobacterium phlei, Bacillus subtilis, Vibrio parahemolyticus, Escherichia coli, Pseudomonas aeruginosa, and Proteus vulgaris. Among them, compound 416 showed promising activity against M. phlei with the same MIC values as positive control ciprofloxacin of 12.5 µM, which indicated the antituberculosis potential. Compound 415 showed activities against B. subtilis with MIC value of 100 µM. Compound 416 showed activities against M. phlei with MIC value of 6.25 µM. Ciprofloxacin was positive control shared same MIC values of 1.56 µM against Mycobacterium phlei and Bacillus subtilis [135].

Compound 418 was tested for antimicrobial activities against two human pathogens (E. coli and S. aureus), seven aquatic bacteria (Aeromonas hydrophila, Edwardsiella tarda, Micrococcus luteus, Pseudomonas aeruginosa, Vibrio alginolyticus, Vibrio harveyi, and Vibrio parahaemolyticus). Compound 418 exhibited inhibitory activity against E. coli, and S. aureus with same MIC values of 32 µg/mL. Positive control was chloramphenicol which with MIC values of 2 µg/mL and 1 µg/mL against E. coli, and S. aureus [136].

Antibacterial activity was evaluated against S. aureus and methicillin-resistant S. aureus. Simplicildone K 430 exhibited antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with equal MIC values of 128 μg/mL. Vancomycin was used as a positive control for antibacterial activity and displayed equal MIC values of 0.5 μg/mL against both S. aureus and methicillin-resistant S. aureus [96].

3.1.3. Antiviral Activity

Anti-enterovirus 71 (EV71) was assayed on Vero cells with the CCK-8 (DOjinDo, Kumamoto, Japan) method. The 50% inhibitory concentration (IC₅₀) of the testing compound was calculated using the GraphPad Prism software. Ribavirin was used as the positive control with an IC₅₀ value of 177.0 µM. Vaccinol J 125 exhibited in vitro anti-EV71 with IC₅₀ value of 30.7 µM, and the inhibition effect was stronger than positive control ribavirin [44].

Anti-HIV activities of compound 150 was tested in vitro by HIV-I virus-transfected 293 T cells. At the concentration of 20 μM, 150 showed a weak inhibitory rate of 16.48 ± 6.67%. Efavirenz was used as the positive control, with an inhibitory rate of 88.54 ± 0.45% at the same concentration [47].

3.2. Cytotoxic Activity or Anticancer

Nectrianolins A–C 11, 12, and 13 were evaluated for their in vitro cytotoxicity against HL60 (human leukemia 60) and HeLa cell lines by the MTT method using a published protocol. Compounds 11, 12, and 13 exhibited cytotoxic activity against the HL60 cell line with IC₅₀ values of 1.7 µM, 1.5 µM and 10.1 µM, respectively. Additionally, compounds 11, 12, and 13 exhibited cytotoxicity against the HeLa cell line with IC₅₀ values of 34.7 µM, 16.6 µM and 52.1 µM, respectively [13].

Compounds 29 and 236 were evaluated for their cytotoxic activities against three human tumor cell lines HeLa, HCT116 (Human colon cancer tumor cells), and A549 (Human lung cancer cells), both of them exhibited weak to moderate cytotoxic activities with IC₅₀ values ranging from 21.09 to 55.43 µM (29: 58.75 ± 1.77 µM, 47.75 ± 1.68 µM, 29.58 ± 1.47 µM, 236: 21.18 ± 1.33 µM, 21.04 ± 1.32 µM, 37.33 ± 1.57 µM against HeLa, HCT116 and A549 respectively) [19].

The cytotoxic activity of the isolated compounds 78–79 and 113–114 were tested against Hela cells. Compound 79 showed weak cytotoxic activities against Hela cells with IC₅₀ value of 43.7 ± 0.43 µM. Compound 78 did not show significant cytotoxic activity. As the oxoindoloditerepene epimers, the 3α-epimer 79 was clearly more cytotoxic than the 3β-epimer 78, suggesting that their cytotoxic activity depended on their stereochemistry. The acetoxy derivatives 113 and 114 showed weak cytotoxic activities against Hela cells with IC₅₀ values of 83.8 ± 5.2 µM and 53.5 ± 2.1 µM respectively [35].

Since many triterpenoids isolated from plants of the family Schisandraceae are reported to reduce the risk of liver diseases and cancer, compounds 93–100 were evaluated for in vitro cytotoxicity against human hepaticellular liver carcinoma cell (HepG2), according to the MTT method, with cisplatin as the positive control (IC₅₀ value of 9.8 ± 0.21 µM). Compounds 93–100, showed moderate cytotoxic activity with IC₅₀ values ranging from 14.3 to 21.3 µM (IC₅₀ values of compounds 93: 15.6 µM, 94: 16.1 µM, 95: 16.4 µM, 96: 15.4 µM, 97: 17.9 µM, 98: 18.8 µM, 99: 14.3 µM, 100: 21.3 µM). It should be noted that those metabolites 93–100 produced during fermentation showed stronger cytotoxicity to HepG2 cell line than that of nigranoic acid, the main component of non-fermented K. angustifolia [39].

The in vitro cytotoxicity of compound 119 against the human acute monocytic leukemia cell line (THP-1) was evaluated using a resazurin-based assay and an ATPlite assay. Compound 119 demonstrated marked cytotoxicity against the human acute monocytic leukemia cell line (THP-1) with the IC₅₀ value of 8.0 µM [42].

The in vitro cytotoxicity assay was performed with some cancer cells including the mouse fibroblast cell line L929, cervix carcinoma cell line KB-3-1, human breast adenocarcinoma MCF-7, human prostate cancer PC-3, squamous carcinoma A431, human lung carcinoma A549 and ovarian carcinoma SKOV-3. Compounds 169, 170 showed significant cytotoxicity against the mouse fibroblast cell line L929 and the cervix carcinoma cell line KB-3-1, with IC₅₀ values ranging from 6.3 to 23 µg/mL (169: 23 µg/mL against the mouse fibroblast cell line L929, 22 µg/mL against cervix carcinoma cell line KB-3-1 170: 6.3 µg/mL against the mouse fibroblast cell line L929, 11 µg/mL against cervix carcinoma cell line KB-3-1). Compound 170 showed the strongest cytotoxicity among the metabolites tested against human breast adenocarcinoma MCF-7 cells with IC₅₀ value of 1.5 µg/mL. Besides, compound 170 showed cytotoxicity against squamous carcinoma A431, human lung carcinoma A549 and ovarian carcinoma SKOV-3 with IC₅₀ values of 6.5 µg/mL, 16 µg/mL and 6.5 µg/mL. Epothilon B was used as positive control (IC₅₀ values against 7 cancer cells mentioned above were 0. 8 ng/mL, 0. 06 ng/mL, 0.04 ng/mL, 1.1 ng/mL, 0.1 ng/mL, 2 ng/mL and 0.12 ng/mL) [52].

Standard MTT assays employing MDA-MB-435 and A549 cell lines were performed. The IC₅₀ was determined by a 50% reduction of the absorbance in the control assay. Compound 176 exhibited cytotoxicity against MDA-MB-435 and A549 cell lines with IC₅₀ values of 16.82 and 20.75 µM, respectively. The positive control was used by Epirubicin (EPI) with IC₅₀ values of 0.26 and 5.60 µM against MDA-MB-435 and A549 cell lines [54].

All isolated new compounds 190–194 were evaluated for their cytotoxic activities against various cancer cell lines, which include A549, Raji, HepG2, MCF-7, HL-60 and K562. Compounds 190–194 displayed in vitro inhibitory activities against the six tumor cell lines to various degrees. Among them, compound 192 showed the most potent cytotoxicity against all evaluated cell lines with IC₅₀ values of 1.2, 2.0, 1.6, 2.2, 1.0 and 1.2 μg/mL, respectively, which were even stronger than an anti-tumor agent DDP used as positive control (IC₅₀ values against six cell lines: 2.8 μg/mL, 2.1 μg/mL, 2.6 μg/mL, 2.4 μg/mL, 2.1 μg/mL and 2.2 μg/mL). Compounds 193 and 194 also exhibited moderate growth inhibition against six tested cell lines with IC₅₀ 6.3–26.8 μg/mL for 193 and IC₅₀ 3.1–24.4 μg/mL for 194. However, compounds 190 and 191 were effective only against HL-60 and K562 cell lines (IC₅₀ value: 190: 24.1 μg/mL, 10.7 μg/mL 191: 24.2 μg/mL, 23.1 μg/mL). These results indicated that the keto or hemiketal functionality (e.g., 192–195) would play an important role in cytotoxic activity. Additionally, the activity profile reflected that the hydroxyl-substituted position had a different impact on cytotoxic activity. 2-Pyrones were more active as cytotoxic agents if the alkyl chain at C-6 was oxygenated but the addition of the hydroxyl subunit to C-8 and C-9 significantly decreased the activity [59].

The isolated compound 202 was preliminary evaluated for its cytotoxicities against MCF-7, NCI-H460, HepG-2, and SF-268 cell lines with cisplatin as the positive control. The new compound 202 exhibited weak growth inhibitory activity against the tumor cell lines MCF-7 and HepG-2 with IC₅₀ values of 70 and 60 µM, respectively [64].

Cytotoxic activities of compound 209 against HeLa, MCF-7 and A549 cell lines were evaluated by the MTT method. Adriamycin was used as a positive control. The results showed that 209 displayed cytotoxic activity against A549 cell lines with IC₅₀ value of 15.7 μg/mL [66].

Compound 221 was assessed for its antiproliferative activities against the mouse lymphoma (L5178Y) cell line using the in vitro cytotoxicity (MTT) assay and kahalalide F as a standard antiproliferative agent (IC₅₀ = 4.30 µM). Results revealed the new compound, aflaquinolone H (221), exhibited moderate antiproliferative activity (IC₅₀ = 10.3 µM) which highlights the role of the hydroxyl group at C-21 for the antiproliferative activity [71].

Compounds 222–223 were evaluated for in vitro inhibition of cell proliferation by the MTT method using a panel of four human cancer cell lines: NCI-H460 (non-small cell lung cancer), SF-268 (CNS glioma), MCF-7 (breast cancer), and PC-3 (prostate adenocarcinoma) cells. Compounds 222 and 223 showed moderate cytotoxicity against four human cancer cell lines with IC₅₀ values of 18.63 ± 1.82, 20.23 ± 2.15, 23.53 ± 2.33 and 20.48 ± 2.04 µM, and 16.47 ± 1.63, 17.57 ± 2.12 20.79 ± 2.39 and 19.43 ± 2.02 µM, respectively, while compound D (Figure 13) was found to be inactive (>50 µM), which suggested -NH₂ group might play a very important role for their cytotoxicity. Doxorubicin (Adriamycin) was used as positive control in this assay (IC₅₀ values against the 4 human cancer cell lines: 0.43 ± 0.12 µM, 0.61 ± 0.09 µM, 0.41 ± 0.11 µM and 0.25 ± 0.08 µM respectively) [72].

Compound 241 was also tested for cytotoxicity against SH-SY5Y (human glioma cell lines), HeLa (cervical epithelial cells), HCT116 (human colon cancer cells), HepG2 (human hepatocellular carcinoma cells), A549 (human lung cancer cells), and MCF7 (human breast cancer cells). Compound 241 showed weak cytotoxic effects against HeLa cells with IC₅₀ value of 97.4 μM, while the positive control cisplatin showed IC₅₀ value of 21.1 µM [78].

The cytotoxicity of compound 244 against a human cervical tumor cell line (HeLa) was tested using the MTT assay. Compound 244 presented an IC₅₀ value of 100 μmol/L. Camptothecin was used as positive control and presented an IC₅₀ of 0.12 μmol/L [80].

The cytotoxicities against HBE, THLE, and MDA-MB-231 of compound 252 were evaluated by MTT method. 252 exhibited selective cytotoxicities against MDA-MB-231 with IC₅₀ of 24.6 ±1.3 µg/mL [82].

Compounds 262,426–427 were evaluated for their cytotoxicity against a human leukemia cell line (K562), a colon adenocarcinoma cell line (SW480), and a human liver carcinoma cell line (HepG2). Compounds 262 and 427 showed moderate cytotoxic activity against all the tested cell lines with IC₅₀ ranging from 12.0 to 28.3 µM (IC₅₀ values against K562, SW480, and HepG2 cells: 262: 15.9 (13.1–19.3) µM, 12.0 (8.8–16.4) µM, 28.3 (23.2–34.6) µM 427: 20.6 (14.0–30.3) µM, 20.3 (16.8–24.4) µM, 20.4 (16.4–25.4) µM). In addition, compound 426 showed moderate cytotoxicity towards K562 cells with an IC₅₀ value of 18.7 µg/mL. Cisplatin was used as the positive control with IC₅₀ values of 3.8, 5.5, and 6.8 µM toward K562, SW480, and HepG2 cells, respectively [86].

Compound 281 was evaluated cytotoxic activities against three cancer cell lines HCT 116, HeLa, and MCF7, and displayed strong biological effect against MCF7 with halfmaximal inhibitory concentration (IC₅₀) value at 7.73 ± 0.11 µM compared with the cis-platinum (14.32 ± 1.01 µM) [91].

The isolated compound 287 was examined for cytotoxic activity by MTT assay. Camptothecin was used as positive control for HL60 with IC₅₀ = 23.6 nM. 287 exhibited cytotoxicity against human promyelocytic leukemia HL60 cells with IC₅₀ value of 1.33 µM. The higher cytotoxicity of 287 and E (Figure 13) compared to that of the related compounds F (Figure 13) and G (Figure 13) was attributed to their increased cell membrane permeability due to the presence of the hydroxyl group [69].

Compound 288 was investigated for its cytotoxicities against SMMC-7721 cell by MTT method. The results showed that 288 inhibited SMMC-7721 cells proliferation in a dose-dependent manner (100 µM, 50 µM, 25 µM, 12.5 µM, 6.25 µM), with IC₅₀ of 61 + 2.2 µM [31].

The cytotoxicities of compound 297 were tested by using human promyelocytic leukemia HL-60, human hepatoma SMMC-7721, non-small cell lung cancer A-549, breast cancer MCF-7 and human colorectal carcinoma SW4801 cell lines, 297 showed cytotoxicity against MCF-7 with the ratio of inhibition at 72% for a concentration at 40 µM (IC₅₀ of positive control Taxol < 0.008 µM) [98].

The cytotoxicities of compound 311 were evaluated against the A549 and HepG2 cell lines by the MTT method. Newly isolated compound 311 showed weak activities with IC₅₀ values of 11.05 µM and 19.15 µM, respectively, against the tested cell lines. Doxorubicin was used as a reference (0.94 µM and 1.16 µM) [103].

The obtained compound 320 was evaluated for its cytotoxic activities against A549 human lung cancer cells and HepG2 human liver cancer cells. Compound 320 exhibited potent cytotoxic activities towards A549 human lung cancer cells and HepG2 human liver cancer cells with IC₅₀ values of 23.73 ± 3.61 µM and 35.73 ± 2.15 µM, respectively [90].

The anti-tumor activities of compounds 336–337 were evaluated against Ramos and H1975 cell lines. 337 displayed the most promising anti-tumor activity against both Ramos and H1975 cell lines with IC₅₀ values of 0.018 µM and 0.252 µM, respectively. Compound 337 may be more effective in anti-tumor activity against Ramos and H1975 than stand drug Ibrutinib and afatinib, with IC₅₀ values of 28.7 µM and 1.97 µM. These findings suggest that compound 337 might be promising lead for leukemia and lung cancer treatments. In addition, 336 also displayed anti-tumor activity against both Ramos and H1975 cell lines with IC₅₀ values of 17.98 and 7.3 µM, respectively [113].

Compound 343 was evaluted for the cytotoxicities against three human tumor cell lines, including a human breast cancer cell line (MDA-MB-435), a human gastric cancer cell line (SGC-7901), and a human lung adenocarcinoma epithelial cell line (A549) by MTT method. It is notable that penochalasin K 343 exhibited remarkable broad-spectrum inhibitory activities against all the tested cell lines (IC₅₀ values against MDA-MB-435, SGC-7901 and A549: 4.65 ± 0.45 µM, 5.32 ± 0.58 µM and 8.73 ± 0.62 µM). Epirubicin was used as a positive control with IC₅₀ values of 0.56 ± 0.06 µM, 0.37 ± 0.11 µM and 0.61 ± 0.05 µM against MDA-MB-435, SGC-7901 and A549 [114].

The cytotoxicity was evaluated by the [3H] thymidine assay using breast cancer (MCF-7) and colon cancer (COLO-205) cell lines. Doxorubicin (10 µg), was used as a positive control with ED₅₀ (50% effective dose) value of 1.8 µg/mL against MCF-7 cell line. Compound 362 showed cytotoxic activity against MCF-7 cell line with ED₅₀ value of >10 µg/mL [116].

Compound 363 was evaluated for its cytototoxicity against different cancer cell lines MOLT-4, A549, MDA-MB-231and MIA PaCa-2 by MTT assay. Interestingly, compound 363 showed considerable cytotoxic potential against the human leukaemia cancer cell line (MOLT-4) with IC₅₀ value of 20 µmol/L, it was not as active as the positive control flavopiridol (IC₅₀ value of 0.2 µmol/L) [117].

Cytotoxicity against four tumor cell lines (A549, HeLa, MCF-7, and THP-1) of compound 365 was evaluated. In the cytotoxic assay, compound 365 displayed weak in vitro cytotoxicity against the THP-1 cell line, with IC₅₀ value of 40.2 µM [118].

The cytotoxic effect of 389 was evaluated in vitro towards ovarian (SK-OV-3), epidermoid (KB), malignantmelanoma (SK-MEL), human breast adenocarcinoma (MCF-7), colorectal adenocarcinoma (HCT-116), and ductal (BT-549) carcinomas. Doxorubicin (positive control) and DMSO (negative control) were used. It had selective and potent effect towards BT-549, MCF-7, SKOV-3, and HCT-116 cell lines with IC₅₀s 0.09 ± 0.05, 21 ± 0.07, 1.23 ± 0.03, and 0.59 ± 0.01 µM, respectively, compared to doxorubicin (IC₅₀s 0.045 ± 0.11, 0.05 ± 0.01, 0.321 ± 0.21, and 0.24 ± 0.04 µM, respectively). Fusarithioamide B (389) may provide a lead molecule for future developing of antitumor and antimicrobial agents [125].

In the cancer cell line cytoxicity assays, compound 395 displayed low activity against human non-small cell lung A549 and human prostate PC3 cell lines (A549: EC₅₀ (concentration for 50% of maximal effect) = 86.4 μM for 395, PC3: EC₅₀ = 40.25 μM for 395. 1.5 mM hydrogen peroxide was used as positive control (100% dead cells), 0.1% dimethyl sulfoxide was used as negative control (100% live cells) [129].

Compounds 396–397 were evaluated for their cytotoxic activity against four human tumor cell lines (SF-268, MCF-7, HepG-2 and A549) by the SRB (Sulforhodamine B) method. As a result, compounds 396, 397 showed weak inhibitory activities against the four tumor cell lines with IC₅₀ values ranging from 30 to 100 µM (IC₅₀ values against SF-268, MCF-7, HepG-2 and A549 396: 41.68 ± 0.88 µM, 37.68 ± 0.3 µM, 48.33 ± 0.1 µM and 53.36 ± 0.91 µM, 397: 69.46 ± 7.08 µM, 97.71 ± 0.72 µM, 79.43 ± 0.63 µM and 0 ≥ 100 µM). Cisplatin was used as a positive control with IC₅₀ values of 3.39 ± 0.29 µM, 3.19 ± 0.12 µM, 2.42 ± 0.14 µM and 1.56 ± 0.08 µM against the four human tumor cell lines [41].

The in vitro cytotoxicity assay was performed according to the MTS method in 96-well microplates. Five human tumor cell lines were used: human myeloid leukemia HL-60, human hepatocellular carcinoma SMMC-7721, lung cancer A-549, breast cancer MCF-7, and human colon cancer SW480, which were obtained from ATCC (Manassas, VA, USA). Cisplatin was used as the positive control for the cancer cell lines (IC₅₀ values against HL-60, A-549, SMMC-7721, MCF-7, and SW480 cell: 4.05 ± 0.11, 19.40 ± 0.71, 14.91 ± 0.36, 22.96 ± 0.58 and 23.15 ± 0.22 μM). Compound 447 demonstrated moderate cytotoxicity against HL-60, A-549, SMMC-7721, MCF-7, and SW480 cell with IC₅₀ values of 15.80, 15.93, 19.42, 19.22, and 23.03 μM, respectively [27].

3.3. Other Activities

α-Glucosidase inhibitors are helpful to prevent deterioration of type 2 diabetes and for the treatment of the disease in the early stage, so the α-glucosidase inhibitory effects of the isolated compounds were evaluated. As a result, compounds 247, 248 exhibited potent α-glucosidase inhibitory activity with IC₅₀ values of 25.8 µM, 54.6 µM, respectively, which were much better than acarbose (IC₅₀ of 703.8 µM) as a positive control. Compounds 7 and 249 showed moderate inhibitory activity against α-glucosidase with IC₅₀ values of 188.7 µM and 178.5 µM, respectively. The results indicated that the configureuration at C-5 in compounds 6 and 7 might affect α-glucosidase inhibitory activity. Moreover, the methoxy group at C-15 in the lasiodiplodin derivatives decreased the activity (248 vs. H (Figure 13)). For compounds 247, I (Figure 13), J (Figure 13), and K (Figure 13), compounds 247 and I showed potent α-glucosidase inhibitory effects, whereas J and K were inactive, which attested that the position of the hydroxyl group had a significant impact on the activity [10].

AChE inhibitory activities of the compound 14 were assayed by the spectrophotometric method. Compound 14 indicated anti-AChE activity with inhibition ratio at 35% in the concentration of 50 μM. Tacrine (Sigma, purity > 99%) was used as a positive control of inhibition ratio at 52.63% with the concentration of 0.333 μM [14].

The inhibition of the marine phytoplankton Chattonella marina, Heterosigma akashiwo, Karlodinium veneficum, and Prorocentrum donghaiense by 31–37 were assayed. The results showed that 32–34 were more active to C. marina, K. veneficum, and P. donghaiense than 31 and 35–37 (IC₅₀ against C. Marina, H. akashiwo, K. veneficum and P. donghaiense: 31: 11, 4.6, 12 and 23 μg/mL 32: 1.2, 4.3, 1.3 and 5.7 μg/mL 33: 3.3, 9.2, 1.5 and 6.8 μg/mL 34: 0.93, 7.8, 2.7 and 4.9 μg/mL 35: 6.7, 2.9, 6.6 and 10 μg/mL 36: 5.4, 5.8, 8.4 and 14 μg/mL 37: 3.7, 6.9, 9.4 and 12 μg/mL). A structure-activity relationship analysis revealed that the phenyl group in 32–34 may contribute to their inhibitory ability, but the isomerization at C-9 and/or C-11 of 32–37 only has slight influences on their activities. K2Cr2O7 was used as positive control with IC₅₀ values of 0.46, 0.98, 0.89 and 1.9 μg/mL, respectively [21].

The biological effects of compound 38 were evaluated on the seedling growth of Arabidopsis thaliana, and 38 displayed an effect on the root growth but no remarkable inhibition of leaf growth in Arabidopsis thaliana [22].

The antioxidant activity was estimated by using adapted 2, 2′-diphenyl-b-picrylhydrazyl (DPPH) method. Ascorbic acid (IC₅₀ = 2.0 μM) and methanol were used as positive and negative controls, respectively. 49 and 413 showed remarkable antioxidant activity with IC₅₀ values of 2.50 and 5.75 μM respectively [24].

The biological activity properties of compounds 63–65 were evaluated for inhibitory activity against pancreatic lipase. Compounds 63–65 displayed potent inhibition in the assay with IC₅₀ values of 2.83 ± 0.52, 5.45 ± 0.69, and 6.63 ± 0.89 μM, respectively, compared to the standard kaempferol (1.50 ± 0.21 μM) [29].

Nuclear transcription factor (PXR) can regulate a suite of genes involved in the metabolism, transport, and elimination of their substances, such as CYP3A4 and MRP, therefore, it is regarded as an important target to treat cholestatic liver disorders. So compound 76 was assayed for agonistic effects on PXR. Compound 76 displayed the significant agonistic effect on PXR with EC₅₀ value of 134.91 ± 2.01 nM [33].

Brine shrimp inhibiting assay was assayed. Compound 80 displayed brine shrimp inhibiting activities with IC₅₀ value of 10.1 μmol/mL. The SDS (sodium dodecyl sulfate) was employed as positive control and its inhibiting ratio was 95% for brine shrimp and LC₅₀ 0.6 μmol/mL [36].

Monitoring the NO level in LPS-activated cells has become a common approach for evaluating the potential anti-inflammatory activities of compounds. Isolates 82–92 were evaluated for their inhibitory activity against NO production in LPS-activated RAW 264.7 marcrophages, while indomethacin was used as a positive control. Compounds 89–91 exhibited inhibitory effects with IC₅₀ values of 21, 24 and 16 μM, respectively, which are lower than that of the positive control indomethacin (IC₅₀ = 38 ± 1 μM), while compound 85 exhibited moderate inhibition with an IC₅₀ value of 42 μM. Preliminary structure–activity relationships revealed that the analogues with the S absolute configureuration at C-18 (e.g., 89–91) significantly enhanced the activity, as exemplified by compound 89 showing inhibition against NO production in RAW 264.7 marcrophage cells with an IC₅₀ value of 21 μM, whereas compound 87 exerted less than 40% inhibition at 50 μM. In addition, all isolated compounds (82–92) were tested for their inhibitory activity of Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB). Compound 89 displayed inhibition with an IC₅₀ value of 19 μM, comparable to the positive control (oleanolic acid, IC₅₀ = 22 ± 1 μM). Compounds 83, 85, 86 and 90 showed moderate inhibitory activity of MptpB with IC₅₀ values of 39 ± 2 μM, 42 ± 3 μM, 28 ± 1 μM and 35 ± 1 μM, respectively [38].

Compounds 135–146 were evaluated for their inhibitory effects on the NO production in LPS-stimulated RAW264.7 microglial cells using Griess assay. Meanwhile, the effects of compounds 135–146 on cell proliferation/viability were measured using the MTT method. As a result, compounds 138, 139, 142, 143, 145 and 146 exhibited inhibitory activity against NO production with IC₅₀ values in the range of 56.3–98.4 μM (IC₅₀ values of compounds on LPS-stimulated NO production in RAW264.7 macrophage cells 138: 85.2 ± 4.3 µM, 139: 98.4 ± 5.6 µM, 142: 95.9 ± 3.4 µM, 143: 64.8 ± 1.3 µM, 145: 60.0 ± 3.1 µM, 146: 56.3 ± 1.1 µM). Indomethacin was used as a positive control (IC₅₀ = 33.6 ± 1.4 μM) [45].

Measurement of ATP release of thrombin-activated platelets of the isolated compound 168 was investigated by applying D. S. Kim’s method. Compound 168 exhibited inhibitory activities on ATP release of thrombin-activated platelets with IC₅₀ value of 57.6 ± 3.2 μM. Staurosporine served as the positive control with IC₅₀ value of 3.2 ± 0.6 μM [51].

The inhibition of biofilm formation against Staphylococcus aureus DSM 1104 was tested in 96-well tissue microtiter plates. The compounds were tested in concentrations of up to 256 µg/mL. MeOH and cytochalasin B were used as negative and positive control, respectively. Minimum Inhibitory Concentration (MIC) value of 256 µg/mL was observed for metabolite 169 and it showed a weak inhibition of biofilm formation of 20.78% at 256 µg/mL [52].

A colorimetric α-glucosidase (Sigma-Aldrich Co. CAS number: 9001-42-7, E.C 3.2.1.20) assay of compounds 176–180 was performed. 1-deoxynojirimycin (St. Louis, MO, USA) was used as a positive control. In addition, The DPPH radical scavenging assay of these compounds was also conducted with 96-well plates using a revised method. The positive control was used by Vitamin C. Compounds 176–178 showed significant α-glucosidase inhibitory activity with IC₅₀ values of 35.8 μM, 53.3 μM and 60.2 μM, respectively, compared to 62.8 μM for the positive control (1-deoxynojirimycin). Moreover, compound 179 exhibited radical scavenging activity against DPPH with EC₅₀ value of 68.1 μM, the EC₅₀ value of positive control ascorbic acid was 22.3 μM [54].

The tested compounds 200, 276, 344–346 were investigated for their capacity to inhibit biofilm formation in the reference strains of S. aureus, E. faecalis and E. coli. Aacetylquestinol 276, 345 and 200 were found to cause a significant reduction inbiofilm production by E. coli ATCC 25922 with the percentage of biofilm formation: 50.6 ± 17.6%, 23.7 ± 24.8% and 57.6 ± 8.1%, respectively. On the other hand, emodin 344 and 345 showed inhibition of biofilm production in S. aureus ATCC 25923 (21.1 ± 11.5% and 21.8 ± 18.9%). Interestingly, 345, which is the most effective in inhibiting biofilm formation in E. coli ATCC 25922, also caused nearly 80% reduction of the biofilm production in S. aureus ATCC 25923 [62].

Compound 207 was evaluated for its acetylcholinesterase (AChE) inhibitory activity using the Ellman colorimetric method, it showed weak AChE inhibitory activity with the inhibition ratio of 11.9% at the concentration of 50 μmol/mL [65].

The anti-inflammatory activities of the isolated compounds 210–211 were evaluated by measuring the inhibitory activity of nitric oxide (NO) production levels in the lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells. 210–211 exhibited moderate inhibitory activities on NO production in LPS-stimulated RAW264.7 cells without cell cytotoxicities [67].

The transformed products 224–225 and the parent compound L (Figure 13) were evaluated for the neuroprotective activity using the LPS-induced neuro-inflammation injury assay. 224–225 exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with EC₅₀ values of 35.3 ± 0.9 nM and 32.1 ± 0.9 nM, respectively, while L (EC₅₀ = 8.3 ± 0.4 nM) exhibited comparable activity with the positive control ibuprofen (EC₅₀ = 19.4 ± 0.7 nM). The transformed products 224–225 and L all exhibited considerable neuroprotective activity in the invitro LPS-induced neuro-inflammation injury assay, suggesting that the hupA moiety shared by these compounds may be used as a lead structure for the development of neuroprotective drugs [73].

The artificial insect mixed drug method was used to determine the insecticidal activities of compound 228. Compound 228 displayed remarkable insecticidal activities against first instar larvae of the cotton bollworm Helicoverpa armigera with mortality rates of 70.2%. Commercially-available matrine was used as positive control, causing 87.4% mortality rate under the same conditions. Acute cytotoxicity towards hatching rate, malformation and mortality of zebrafish embryos or larvae were also performed. Compounds 227 and 228 significantly decreased the hatching rate of zebrafish embryos, compound 228, used at concentrations of 5–100 μg/L, decreased the hatching rate of zebrafish embryos to below 20% [74].

The potential phytotoxicity of 246 against lettuce seedlings (Lactuca sativa L.) was studied. Aqueous solutions of 246 ranging between 25 and 200 μg mL⁻¹, were assayed for its effects on seed germination, root length, and shoot length of the lettuce. Compound 246 showed the most robust inhibitory effect on root growth. Compound 246 inhibited root growth by 50% at a concentration of 25 µg/mL. In addition, the highest concentration of 246 (200 µg/mL) strongly exerted an inhibitory effect on seed germination (90% inhibition) [81].

Compounds 256–257 were investigated for their inhibitory activities against the LPS-activated production of NO in RAW264.7 cells using the Griess assay with indomethacin as a positive control (IC₅₀ = 37.5 ± 1.6 μM). The effects of compounds on cell proliferation/viability were determined using MTT method, and none of the test compounds exhibited cytotoxicity at their effective concentrations. Compounds 256 and 257 showed strong inhibitory effects on the production of NO, with IC₅₀ values of 0.78 ± 0.06 and 1.26 ± 0.11 μM, respectively [84].

In vitro anti-inflammatory effects of compounds 258–261 were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. 258–261 exhibited excellent inhibitory effects on the production of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) in LPS-induced macrophages with the IC₅₀ values ranging from 16.21 ± 1.62 μM to 35.23 ± 3.32 μM, from 19.83 ± 1.82 μM to 42.57 ± 4.56 μM, from 16.78 ± 1.65 μM to 38.15 ± 3.67 μM, respectively, similar with the positive control indomethacin. Those results indicated that, terrusnolides A–D (258–261) might play a significant role as a lead compound in the study of anti-inflammatory agents. In addition, compounds 258–261 were also investigated for the inhibitory activities against BACE1 by M-2420 method and acetylcholin esterase (AchE) using Ellman’s method. Compound 260 exhibited weak AchE inhibitory activity with IC₅₀ value of 32.56 ± 3.16 µM, compound 261 exhibited weak BACE1 inhibitory activity with IC₅₀ value of 37.45 ± 4.56 µM. LY2811376 and Donepezil were used as the positive control in BACE1 and AchE inhibitory assay with IC₅₀ values of 0.25 ± 0.04 µM and 0.05 ± 0.01 µM, respectively [85].

The Indoleamine 2,3-dioxygenase (IDO) inhibitory activity assay of compounds 284–286 were carried out. The results showed that compound 285 possessed significant inhibitory activity against IDO with IC₅₀ value of 0.11 μM. Epacadostat, as the positive control, was one of the most potent IDO inhibitors with IC₅₀ value of 0.05 μM. For compounds 284 and 286, they showed relatively strong inhibitory activity with IC₅₀ values of 1.47 μM and 6.36 μM, respectively [92].

NF-κB has been considered as an attractive therapeutic target for the cancer research. Compound 288 was investigated for its effects on NF-κB pathway by reporter gene assay. The results showed that it could activate the NF-κB pathway with increments in the relative luciferase activity at a concentration of 50 μM [93].

The phytotoxic activities of 295 and 296 were investigated by seed germination test on lettuce (Lactuca sativa L.) with 2,4-dichlorophenoxyacetic acid (0.3 µg/mL) as the positive control. Compounds 295 and 296 each inhibited the growth of both roots and hypocotyls at 30 µg/mL. Furthermore, 295 suppressed seed germination at 100 µg/mL [97].

Acetylcholinesterase (AChE) inhibitory activities of the compound 302 were assayed by the spectrophotometric method developed by Ellman with modification. 302 showed weak AChE inhibitory activity (The percentage inhibition was at 20%~60% in 50 μM) [99].

The 5-lipoxygenase (5-LOX) inhibitory potential of 306–308 from Fusarium sp. was assessed in an attempt to explore their activity against 5-LOX. It is noteworthy that 306 displayed prominent 5-LOX inhibitory activity with IC₅₀ value of 3.61 μM, compared to that of indomethacin (IC₅₀ = 1.17 μM), while 307 and 308 had moderate activity with IC₅₀ values of 7.01 μM and 4.79 μM, respectively [101].

α-Glucosidase inhibitory activity was performed in the 96-well plates and acarbose was used as the positive compound. In the inhibitory assay against α-glucosidase, compound 313 displayed moderate activities [104].

The anti-inflammatory activities of selected isolated 4 compounds 314–317 were evaluated as inhibitory activities against lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW264.7 cell lines. Compound 317 showed the most NO inhibitory effects, with the inhibition of 17.4% NO production in LPS stimulated RAW264.7 cells at 10 μM. At the same concentration, compound 315 significantly inhibited the NO production, with 11.2% inhibitory rate. Compound 314 showed weak NO inhibitory effects at 10 μM, with inhibitory rates of 6.5%. At the same concentration, quercetin, the positive control, inhibited NO production to 12.9% [105].

The Superoxide anion radical scavenging activity of compound 331 was investigated. It displayed strong antioxidant activity with EC₅₀ value of 1.08 mg/mL on superoxide anion racdicals. Ascorbic acid (Vc) was used as positive control with EC₅₀ value of 0.33 mg/mL [111].

Compounds 333 and 334 were subjected to motility inhibitory and zoosporicidal activity tests against P. capsici (Phomopsis capsici). Compounds 333 and 334 showed more than 50% motility inhibitory activity (IC₅₀) at a concentration of 50−100 μg/mL [112].

Human carboxylesterases (hCE 1 and hCE 2) are the important enzymes that hydrolyze chemicals with functional groups, such as a carboxylic acid ester and amide, and they are known to play vital roles in drug metabolism and insecticide detoxication. The isolated compounds 379–385 were assayed for their inhibitory activities against hCE 2. Loperamide was used as a positive control with IC₅₀ value of 1.31 ± 0.09 µM. Compounds 379, and 383–385 displayed significant inhibitory activities against hCE 2 with IC₅₀ values of 10.43 ± 0.51, 6.69 ± 0.85, 12.36 ± 1.27, 18.25 ± 1.78 µM, respectively [94].

The inhibitory effects on human carboxylesterases (hCE1, hCE2) of compound 386 were evaluated. The results demonstrated that bysspectin A 386 was a novel and highly selective inhibitor against hCE2 with the IC₅₀ value of 2.01 µM. Docking simulation also demonstrated that active compound 386 created interaction with the Ser-288 (the catalytic amino-acid in the catalytic cavity) of hCE2 via hydrogen bonding, revealing its highly selective inhibition toward hCE2 [124].

Compounds 392–393 were also evaluated for growth inhibition activity against newly hatched larvae of H. armigera Hubner. Compounds 392 and 393 showed growth inhibition activities against newly hatched larvae of H. armigera Hubner with the IC₅₀ values of 150 and 100 µg/mL, respectively. Azadirachtin was used as positive control with the IC₅₀ value of 25 µg/mL [128].

Antioxidant activity of the compound 403 was determined by DPPH assay and compared with the positive control BHT. Compound 403 showed moderate antioxidant activities with IC₅₀ value of 120.1 ± 11.7 μg/mL [131].

The new compounds 406–407 were subjected for determination of the xanthine oxidase (XO) inhibitory activity using microtiter plate based NBT assay. Allopurinol was used as a positive control with IC₅₀ value of 0.18 ± 0.02 µg/mL. 406 and 407 showed XO inhibitory activity with IC₅₀ values of 2.81 ± 0.71 and 0.41 ± 0.1 µg/mL, respectively. The oxidized form of 406 also showed high XO inhibition with IC₅₀ value of 0.35 ± 0.13 µg/mL [133].

Compound 421 was tested for osteoclastic differentiation activity using murine macrophage derived RAW264.7 cells. 421 significantly increased the number of mature osteoclasts at the comparable levels to the positive control of kenpaullone, compared to the negative control (DMSO), suggesting that 421 activated a signaling pathway in osteoclastic differentiation [139].

Phtotoxicity assay against lettuce seedlings of compound 432 was carried out using a published protocol. The new compound (−)-dihydrovertinolide 432 exhibited phytotoxicity against lettuce seedlings at a concentration of 50 mg/L [140].

All new compounds were tested for in vitro anti-inflammatory activities against nitric oxide production in liposaccharide (LPS)-induced RAW264.7 cells, and dexamethasone was used as the positive control. Compound 436 showed significant inhibitory activity against NO production in LPS-induced RAW264.7 cells with an IC₅₀ value of 1.9 μM. They were also evaluated for in vitro antidiabetic activities based on the inhibition of alpha-glucosidase, PTP1b, and XOD. Compounds 437 and 441 showed moderate inhibitory activities toward XOD and PTP1b, respectively, at 10 μM with inhibition rates of 67% and 76% [87].

New compound 447 was tested for acetylcholinesterase (AChE) inhibitory activities using the Ellman method with tacrine as the positive control. The results revealed that compound 447 showed weak AChE inhibitory activity wth IC₅₀ value of 23.85 ± 0.20 μM. Tacrine are the positive control used to estimate AChE inhibitory activity with IC₅₀ value of 0.26 ± 0.02 μM [27].

All information about the new compounds are briefly summarized in the Table 1 below.

4. Conclusions From 2017–2019, a total of 449 new secondary metabolites isolated from plant endophytic fungi using different culture method like common culture, co-culture with bacteria, addition of metal ions and so on, were summarized in this review. These compounds have a variety of unique structures, the difference in structure leads to various biological activities of these compounds. Some of these metabolites display significant antimicrobial effects, cytotoxic activities, antioxidant activities and other biological activities, which indicate that they have potential to be agents to treat some diseases. In this review, structure-activity relationships of some compounds were also reviewed. According to genome sequencing, a lot of microorganisms have the potential to produce secondary metabolites with novel structures. However, many fungal gene clusters may be silent under standard laboratory growth conditions. As a result, some pathways to yield secondary metabolites cannot be expressed. Therefore, activating these pathways means that we can get more novel compounds. The approach of microorganism co-culture, involving the cultivation of two or more microorganisms in the same lab environment can do a favour for us. Interestingly, 29 new compounds summarized above were obtained through co-culture of bacteria and fungi or two fungi. Besides, by adding CuCl₂ into fermentation medium of an endophytic fungus P. citrinum 46, two compounds were isolated. The results showed that adding Cu²⁺ into medium to activate silent fungal metabolic pathways can increase the discovery of new compounds. Because the compounds mentioned above were isolated from endophytic fungi in different parts of different plants in different regions, they have a variety of structures and biological activities. In addition to anti-tumor and anti-microbial activities, some compounds also exhibit unique biological activities. Among them, 7 compounds showed weak to moderate AChE inhibitory activity. Some compounds exhibited moderate to potent α-glucosidase inhibitory activity compared with those of positive control. By using adapted 2,2′-diphenyl-b-picrylhydrazyl (DPPH) method, a few of compounds were found to show moderate to remarkable antioxidant activity. Some of them also showed weak to significant inhibitory activity against NO production in LPS-induced RAW264.7 cells. The biological activity properties of 18 compounds were evaluated for inhibitory activity against some enzymes like pancreatic lipase, the 5-lipoxygenase (5-LOX), the Indoleamine 2,3-dioxygenase (IDO), Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB), the xanthine oxidase (XO) and so on, they showed weak to high inhibition. Endophytic fungi isolated from different parts of plants are a huge treasure house on account of the discovery of novel secondary metabolites with biological activities and unique structures. Since the endophyte resources were discovered, more and more researches have been conducted on them. Just from my review article, the new secondary metabolites isolated from plant endophytes during the three years from 2017 to 2019 were counted. Among them, 38 articles were published in 2017, 136 new compounds were obtained; 39 articles were published in 2018, 117 new compounds were obtained; 57 articles were published in 2019, and 196 new compounds were obtained. It can be discovered that in the past three years, the research trend of plant endophytes and their metabolites have increased year by year. The more new compounds obtained, the greater the possibility of screening compounds with excellent biological activity. This is also an important significance for researchers to study plant endophytes. Through this review, i hope to arouse more people’s interest and attention in this field and screen out compounds with good biological activities to create a better life for mankind by utilizing endophytes resources.

Figure 1. Percentage of metabolites synthesized by endophytes.

Figure 2. Chemical structures of sesquiterpenoids and derivatives.

Figure 2. Chemical structures of sesquiterpenoids and derivatives.

Figure 2. Chemical structures of sesquiterpenoids and derivatives.

Figure 3. Chemical structures of diterpenoids and derivatives.

Figure 4. Chemical structures of other terpenoids and derivatives.

Figure 4. Chemical structures of other terpenoids and derivatives.

Figure 5. Chemical structures of polyketides.

Figure 5. Chemical structures of polyketides.

Figure 6. Chemical structures of other ketones.

Figure 7. Chemical structures of alkaloids and their derivatives.

Figure 8. Chemical structures of penylpropanoids and their derivatives.

Figure 9. Chemical structures of lactones.

Figure 9. Chemical structures of lactones.

Figure 10. Chemical structures of anthraquinones.

Figure 10. Chemical structures of anthraquinones.

Figure 11. Chemical structures of sterides.

Figure 12. Chemical structures of other new compounds.

Figure 12. Chemical structures of other new compounds.

Figure 12. Chemical structures of other new compounds.

Figure 12. Chemical structures of other new compounds.

Figure 12. Chemical structures of other new compounds.

Figure 13. Chemical structures of known compounds.

Compound	Molecular Formula	Degree of Unsaturation	Color and Morphology	Endophytic Fungus	Host Plant	Site and Nation	Biological Activity	Ref.
Terpenoids Sesquiterpenoids and derivatives
1	C19H26O7	7	brown oil	Pestalotiopsissp.T	lichen Cetraria islandica (L.) Ach.	Yunnan Province, China	Inhibit the growth of plant pathogenic fungus (1,5)	[9]
2	C21H28O8	8
3	C21H30O8	7
4	C21H28O8	8
5	C19H26O7	7
6	C15H20O4	6	white powder	Co-culture Strain 307: Trichoderma sp. the stem bark of Clerodendrum inerme Bacterium B2: Acinetobacter johnsonii From an aquaculture pond		Guangdong Province, China	Show moderate inhibitory activity against α-glucosidase (7)	[10]
7	C15H20O4	6
8	C15H24O2	4	colorless gum	Trichoderma atroviride	bulb of Lycoris radiata.	Hubei Province China	Inactive	[11]
9	C15H26O3	3	white amorphous powder	Co-culture Pestalotiopsis sp. fruits of Drepanocarpus lunatus (Fabaceae) Bacillus subtilis			Weak antibacterial activities (9)	[12]
10	C15H24O3	4	colorless oi
11	C22H32O5	7	colorless crystal	Nectria pseudotrichia 120-1NP	Inner tissue of Gliricidia sepium healthy stem		Cytotoxicity (11–13)	[13]
12	C26H38O7	8	yellow oil
13	C15H26O	3	yellow oil
14	C15H26O3	3		Co-culture Nigrospora oryzae Irpex lacteus	seeds of Dendrobium officinale	Yunnan Province, China	Anti-AChE activity	[14]
15	C15H26O2	3	white powder	Emericella sp. XL 029	leaves of Panax notoginseng	Hebei province, China	Antifungal activity Antibacterial activity (15,16)	[15]
16	C15H26O3	3	colorless oil
17	C19H24O4	8	colorless oil	Trichothecium crotocinigenum			Antiphytopathogenic activity (17–20)	[16]
18	C19H25ClO5	7	colorless crystals
19	C22H28O5	9	colorless crystals
20
21	C15H22O4	5	colorless oil	Trichoderma atroviride S361	Bark of Cephalotaxus fortunei	Zhejiang province, China	Inactive	[17]
22	C15H20O4	6	white amorphous powder	Aspergillus sp. xy02	leaves of mangrove Xylocarpus moluccensis	Trang Province, Thailand	Antibacterial activity (23–24,26,28)	[18]
23
24
25
26			colorless oil
27
28
29	C15H24O3	4	colorless oil	Pestalotiopsis adusta	stem bark of medicinal plant Sinopodophyllum hexandrum (Royle) Ying	Qinling Mountains China	Weak to moderate cytotoxic activity	[19]
30	C15H26O2	3	colorless oil	F. proliferatum AF-04	green Chinese onion	Lanzhou, China		[20]
31	C14H24O3	3	colorless crystals	Trichoderma asperellum A-YMD-9–2	marine Red alga Gracilaria verrucosa	Yangma Island, Yantai, China	Potent inhibition of several marine phytoplankton species 31–37	[21]
32	C14H20O2	5	colorless oil
33
34
35	C22H37NO7	5	colorless oil
36
37
38	C15H24O4	4	crystal powder	Alternaria oxytropis	desert plant locoweed Oxytropis glabra	Inner Mongolia, China	Displayed an effect on the root growth in Arabidopsis thaliana (38)	[22]
39			colourless oil
40	C15H22O4	5	colourless oil
41	C15H24O5	4	crystal powder
42	C15H22O3	5	colourless oil
43	C15H24O5	4
44	C15H26O4	3
45
46	C15H26O3	3
47
48	C15H22O3	5	colorless crystal	Pleosporales sp. SK7	mangrove plant Kandelia candel	Guangxi Province, China		[23]
49	C15H22O4	5	yellowish needle crystals	Irpex lacteus DR10-1	waterlogging tolerant plant D. chinense	Chongqing China	Antioxidant activity Antibacterial activity	[24]
50	C15H16O3	8	colorless crystals	Trichoderma virens QA-8	fresh inner tissue of the medicinal plant Artemisia argyi	Hubei Province, China	Antibacterial (50–52,55) Antifungal activity (50–55)	[25]
51	C15H16O4	8	colorless oil
52	C15H22O2	5	amorphous powder
53	C15H22O3	5	amorphous powder
54	C15H24O3	4	colorless oil
55	C14H16O4	7	amorphous powder
56	C15H26O2	3	colorless needle	Alternaria alternate	leaves of Psidium littorale Raddi	Fujian Province, China		[26]
57	C15H22O3	5	colorless oil	Epicoccum sp. YUD17002 & Armillaria sp.	rhizomes of the underground portion of Gastrodia elata	Yunnan Province, China		[27]
58	C15H24O4	4
59	C15H22O2	5
60	C15H22O3	5
61	C15H24O4	4	white amorphous powder
62	C29H42O9	9	sticky and optically active oi	Colletotrichum gloeosporioides	Cameroonian medicinal plant Trichilia monadelpha (Meliaceae)	Yaounde, Central region, Cameroon		[28]
63	C17H22O7	7	white powder	Penicillium purpurogenum IMM003	leaf tissue of the medicinal plant Edgeworthia chrysantha.	China	Show significant inhibitory activity against pancreatic lipase	[29]
64	C17H20O7	8	colorless crystals
65	C16H20O6	7
66	C16H24O3	4	yellow oil	Fusarium oxysporum ZZP-R1	coastal plant Rumex madaio Makino	Putuo Island (Zhoushan, China)	Moderate antibacterial effect	[30]
Terpenoids Diterpenoids
67	C20H30O6	6	colorless oil	Nectria pseudotrichia 120-1NP	healthy stem of Gliricidia sepium	Yogyakarta, Indonesia		[31]
68	C28H39NO3	10	amorphous powder	Drechmeria sp.	root of Panax notoginseng	Yunnan, China	Display inhibitory effect (69) Weak antimicrobial effects. (68,70,74)	[32]
69	C28H37NO5	11
70	C33H45NO5	12
71	C32H43NO7	12
72	C32H43NO7	12
73	C33H45NO7	12
74	C27H33NO5	12
75	C32H33NO9	17	amorphous powder	Drechmeria sp.	root of Panax notoginseng	Yunnan province, China	Display the significant agonistic effect on pregnane X receptor (PXR) (76)	[33]
76	C32H41NO6	13
77	C26H40O5	7	colorless oil	Neosartorya fifischeri JS0553	Plant G. littoralis	Suncheon, Korea		[34]
78	C28H39NO3	10	Pale yellow oil	Aspergillus versicolor	fruits of the mangrove Avicennia marina	Red Sea, Egypt	Weak cytotoxic activity (79)	[35]
79
80	C20H26O4	8	colorless crystals	Xylaralyce sp.	healthy leaves of Distylium chinense	China	Display brine shrimp inhibiting activity	[36]
81	C20H26O5	8	colorless crystals	Apiospora montagnei	lichen Cladonia sp.			[37]
Terpenoids Other terpenoids
82	C26H37NO3	9	colorless oil	Aspergillus sp. ZJ-68	fresh leaves of the mangrove plant Kandelia candel	Guangdong Province, China.	Exhibit inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells (89–91) Show comparable inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase B (89)	[38]
83	C25H35NO3	9
84	C25H35NO2	9
85	C26H39NO3	8
86	C25H34O3	9
87	C25H36O4	8
88	C25H36O4	8
89	C25H36O4	8
90	C25H34O3	9
91	C25H38O5	7
92	C25H38O3	7
93	C30H40O6	11	yellowish needle crystals	Kadsura angustifolia & Penicillium sp. SWUKD4.1850	fresh healthy branches of K. angustifolia	China	Moderate cytotoxic activity (93–100)	[39]
94	C30H40O6	11	white needle crystals
95	C30H40O6	11	white amorphous solid
96	C30H40O6	11
97	C32H44O7	11	white amorphous powder
98	C30H42O6	10	white powder
99	C34H46O8	12	yellow amorphous solid
100	C31H44O6	10	yellow amorphous solid
101	C30H46O6	8	white amorphous powder
102	C17H26O5	5	colorless oil	Phyllosticta capitalensis	leaves of Cephalotaxus fortunei Hook	Shanxi Province, China		[40]
103	C17H24O5	6
104	C17H22O5	7
105	C22H32O6	7
106	C17H26O5	5
107	C15H20O5	6		Aspergillus versicolor			Show weak cytotoxic activities against Hela cells. (113–114)	[35]
108	C15H20O5	6
109	C15H20O5	6	rose-colored oil
110	C17H22O6	7
111	C15H20O5	6
112	C15H20O4	6	colorless oil
113	C17H22O5	7
114	C17H22O5	7
115	C16H24O5	5
116	C21H32O3	6	yellow oil	Fusarium oxysporum ZZP-R1	coastal plant Rumex madaio Makino	Putuo Island (Zhoushan, China)	Antimicrobial activity	[30]
117	C12H20O4	3	yellow oil	Diaporthe lithocarpus A740	from the twigs of medicinal plant Morinda officinalis	Guangdong province China		[41]
Ketones
118	C20H32O4N2	6	white powder	Eupenicillium sp. LG41	Chinese medicinal plant Xanthium sibiricum	China	Cytotoxic activity Antimicrobial activity (Antibacterial)	[42]
119	C38H59O6N	10
120	C12H18O5	4	colorless crystals	Phomopsis sp. sh917	fresh stems of I. eriocalyx var. laxiflflora	Kunming, China		[43]
121	C12H18O5	4	colorless powders
122	C11H12O5	6	Brown needles
123	C20H26O10	8	colorless needles
124	C13H14O5	7	brown solids
125	C17H20O3	8	white amorphous powder	Pestalotiopsis vaccinii (cgmcc3.9199)	branch of mangrove plant Kandelia candel (L.) Druce (Rhizophoraceae)	coastal and estuarine areas of southern China	Anti-enterovirus 7l (EV71)	[44]
126	C14H18O4	6	colorless oil
127	C12H16O4	5
128	C12H18O4	4
129	C12H14O4	6
130	C17H22O4	7
131	C17H24O5	6
132	C18H28O6	5
133	C17H22O5	7
134	C17H22O5	7
135	C11H12O5	6	pale yellow powder	Penicillium chrysogenum MT-12	Huperzia serrata (Thunb. ex Murray) Trev.	Fujian Province, China	Exhibit inhibition of nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells (138,139,142,143,145,146)	[45]
136	C9H8O5	6
137	C10H10O5	6	yellow powder
138	C15H20O6	6
139	C14H16O6	7
140	C15H16O6	8	pale yellow powder
141	C15H18O6	7
142	C15H20O6	6
143	C16H22O7	6	yellow powder
144	C15H20O5	6
145	C15H20O5	6
146	C15H20O5	6
147	C14H12O6	9	yellow powder	Cylindrocarpon sp.	fresh roots of Sapium ellipticum	Haut Plateaux region, Cameroon		[46]
148	C14H12O7	9
149	C13H10O7	9
150	C14H12O6	9	yellow crystals	Phomopsis sp. xy21	leaves of the Thai mangrove Xylocarpus granatum	Trang Province, Thailand	Weak anti-HIV activity (150)	[47]
151	C15H16O7	8	colorless crystals
152	C15H16O7	8	White amorphous solid
153	C15H16O5	8
154	C15H12O6	10
155	C15H10O7	11
156	C17H28O3	4	white powder	Aspergillus flocculus	stem of the medicinal plant Markhamia platycalyx			[48]
157	C10H10O4	6	colorless crystals	Colletotrichum gloeosporioides	mangrove Ceriops tagal	Hainan Province China	Show potent antibacterial activity (157,159)	[49]
158	C10H14O4	4	brown oil
159	C10H12O3	5	white powder
160	C14H18O4	6	amorphous powder	Paraconiothyrium sp. SW-B-1	the seaweed, Chondrus ocellatus Holmes	Yamagata Prefecture, Japan	Show moderate antibacterial activity (164)	[50]
161	C14H18O5	6
162	C14H16O6	7
163	C12H16O6	5
164	C22H20O4	13
165	C14H16O6	7	pale brown, amorphous powder	Alternaria alternata MT-47	medicinal plant of Huperzia serrata	Fujian Province, China	Exhibit inhibitory activity on the ATP release of thrombin-activated platelets (168)	[51]
166	C15H12O8	10	pale yellow amorphous powder
167	C18H18O9	10	white amorphous powder
168	C18H20O9	9
169	C10H11NO4	6	white gum	Chaetosphaeronema achilleae	shoots	English Yew (Taxus baccata), Iran	Weak antifungal activity and antibacterial activity (170) Cytotoxicity (169,170) Biofilm formation (169)	[52]
170	C10H10O5	6
171	C27H38O6	9	colorless oil	Aspergillus porosus	algal			[53]
172	C27H38O6	9
173	C26H36O6	9
174	C26H36O6	9
175	C25H38O3	7	colorless oil	Alternaria alternate	leaves of Psidium littorale Raddi	Fujian Province, China		[26]
176	C29H30O10	15	amorphous powder	Phoma sp. SYSU-SK-7	healthy branch of the marine Kandelia candel	Guangxi Province, China	Show strong antibacterial activity (176) Exhibit significant antifungal and antibacterial activity (177) Show significant α-glucosidase inhibitory activity (176–178) Cytotoxicity (176) Exhibit radical scavenging activity against DPPH (179)	[54]
177	C11H14O4	5	white solid
178	C21H24O7	10
179	C13H12O5	8
180	C11H16O3	4	colourless oil
181	C10H14O3	4		Phomopsis sp. D15a2a	leaves of Alternanthera bettzickiana (Amaranthaceae)	Anambra state of Nigeria		[55]
182	C11H16O4	4
183	C11H16O4	4
184	C23H26O7	11		Penicillium purpurogenum IMM003	fresh healthy leaves of Edgeworthia chrysantha	Zhejiang Province, China		[56]
185	C22H26O6	10
186	C10H8O5	7
187	C18H27NO4	6	colorless gum	Camporesia sambuci FT1061 & Epicoccum sorghinum FT1062	healthy fruit of the plant Rhodomyrtus tomentosa	the Big Island in Hawaii		[57]
188	C14H20O6	5	light yellow solid	Rhytismataceae sp. DAOMC 251461	healthy P. mariana needles	New Brunswick, Canada.	Exhibit moderate antifungal activity (189)	[58]
189	C15H22O6	5
190	C9H12O6	4	colorless plate	Phomopsis asparagi SWUKJ5.2020	fresh, healthy branches of medicinal plant Kadsura angustifolia	Yunnan province China	Exhibit notable cytotoxicity (192–194)	[59]
191	C9H12O5	4
192	C9H10O6	5	colorless crystals
193	C11H14O4	5	colorless plates
194	C11H14O5	5
195	C14H18O4	6	colorless oil	Dendrothyrium variisporum	roots of the Algerian plant Globularia alypum	Ain Touta, Batna 05000 (Algeria)		[60]
196	C18H24O5	7
197	C11H10O5	7	colorless oil	Alternaria sp.	twigs of Morinda offificinalis	Guangdong province China		[61]
198	C12H11O5	8	yellow oil
199	C8H12O3	3	colorless gum	Trichoderma atroviride	bulb of Lycoris radiata	Hubei Province China		[11]
200	C13H14O5	7	yellow viscous liquid	Eurotium chevalieri KUFA 0006	healthy twig of Rhizophora mucronata Poir	Chanthaburi Province, Eastern Thailand	Prevent biofilm formation	[62]
201	C9H14O4	3	colorless gum	Simplicillium sp. PSU-H41	leaf of Hevea brasiliensis	Songkhla Province Thailand		[63]
202	C15H12O8	10	yellowish crystal	Cytospora rhizophorae	Morinda offificinalis	Guangdong province China	Exhibit weak growth inhibitory activity against the tumor cell lines (202)	[64]
203	C14H10O6	10	brown gum
204	C14H8O7	11	yellowish green powder
205	C13H16O5	6	yellow gum	Fusarium sp. HP-2	Chinese agarwood “Qi-Nan”	Hainan Province China	Show weak acetylcholinesterase inhibitory activity (207)	[65]
206	C14H14O4	8	red crystals
207	C16H18O6	8	red solid
208	C18H17ClO7	10	yellowish powder	Penicillium citrinum HL-5126	mangrove Bruguiera sexangula var. rhynchopetala	South China Sea	Display cytotoxic activity (209) Show weak antibacterial activity (208)	[66]
209	C18H18O7	10
210	C13H16O5	6	amorphous white powder	Phoma sp. PF2	Artemisia princeps		Show moderate inhibitory activities on nitric oxide levels (210–211)	[67]
211	C14H18O5	6
212	C25H26O5	13	polar yellow solid	Aspergillus sp. ASCLA	healthy leaf tissue of the medicinal plant Callistemon subulatus		Exert moderate-high activities against Staphylococcus aureus	[68]
213	C12H18O3	4	white powder	Cylindrocarpon sp.	fresh roots of Sapium ellipticum	Haut Plateaux region, Cameroon		[46]
214	C25H28O6	12	yellow oil	Diaporthe lithocarpus A740	twigs of medicinal plant Morinda officinalis.	Guangdong province China		[41]
Alkaloids and their derivatives
215	C26H33O8N	11		Apiospora montagnei	lichen Cladonia sp.			[37]
216	C16H19NO3	8	colorless amorphous solid	Chaetomium globosum CDW7				[69]
217	C17H24N2O3	7	colorless crystals	Penicillium citrinum HL-5126	mangrove Bruguiera sexangula var. rhynchopetala	South China Sea		[66]
218	C13H15NO2	7	colorless powder	Bionectria sp.	seeds of the tropical plant Raphia taedigera	Haut Plateaux region, Cameroon		[70]
219	C16H15NO5	10	yellow powder	Cylindrocarpon sp.	fresh roots of Sapium ellipticum	Haut Plateaux region, Cameroon		[46]
220	C14H21NO5	5	white powder
221	C26H29NO6	13	pale yellow amorphous solid	Aspergillus versicolor	leaves of the Egyptian water hyacinth Eichhornia crassipes	Egypt	Exhibit moderate antiproliferative activity	[71]
222	C17H15NO8	11	white amorphous solid	Pestalotiopsis flavidula	branches of Cinnamomum camphora	Yunnan province china	Moderate cytotoxicity (222–223)	[72]
223
224	C19H24N2O2	9	white amorphous powder	Irpex lacteus-A	medicinal plant Huperzia serrata	Fujian Province China	Show moderate neuroprotective activity (224–225)	[73]
225	C19H24N2O2	9
226	C14H17NO3	7	colorless solid	Alternaria alternate	leaves of Psidium littorale Raddi	Fujian Province, China		[26]
227	C27H31N3O5	14	brilliant yellowish oil	Fusarium sambucinum TE-6L	fresh leaves of cultivated tobacco (N. tabacum L.). N. tabacum L.	Hubei province China	Show potent inhibitory effects (227–228) Exhibit remarkable larvicidal activity (228)	[74]
228	C27H31N3O5	14	white solid
Penylpropanoids and their derivatives
229	C10H14O5	4	clear solid	Mycosphaerellaceae sp. DAOMC 250863	healthy needles from Picea rubens (red spruce) and P. mariana (black spruce)	Eastern Canada	Show modest antibiotic activity to E. coli	[58]
230	C16H18O4	8	light-yellow powder	C. globosum CDW7	Ginkgo biloba	China	Show moderate antifungal activity	[69]
231	C12H14O4	6	colorless amorphous solid	Pestalotiopsis sp. HHL-101	fresh twigs of the mangrove plant Rhizophora stylosa	Hainan Island, China	Exhibit moderate antibacterial activity	[75]
232	C12H12O4	7	white amorphous powder	Nectria pseudotrichia 120–1NP	healthy stem of Gliricidia sepium	Yogyakarta, Indonesia		[31]
233	C13H14O4	7
234	C21H12O12	16	off-white amorphous solid	Aspergillus versicolor	leaves of the Egyptian water hyacinth Eichhornia crassipes	Egypt		[71]
235	C22H14O12	16	yellowish amorphous powder
236	C21H22O6	11	colorless crystals	Pestalotiopsis adusta	stem bark of wild rare medicinal plant Sinopodophyllum hexandrum (Royle) Ying	Qinling Mountains China	Show weak to moderate cytotoxic activity	[19]
237	C13H14O7	7	white solid powder	T. harzianum Fes1712	Rubber Tree Ficus elastica Leaves	China	Exhibit inhibitory activity against Gram-negative bacteria (237–238)	[76]
238
239	C11H12O6	6	white amorphous powder	Penicillium coffeae MA-314	fresh inner tissue of the leaf of marine mangrove plant Laguncularia racemosa	Hainan island, China		[77]
240
241	C18H22O3	8	yellow oil	Diaporthe sp.	branches of Pteroceltis tatarinowii Maxim	Nanjing province, China	Show modest antibacterial activity Weak cytotoxicity	[78]
Lactones
242	C11H10O5	7	yellowish brown solid	Alternaria sp.	seeds of the plant Ziziphus jujuba	Uzbekistan		[79]
243	C16H26O6	4	white, amorphous powder	Phaeoacremonium sp.	leaves of Senna spectabilis	Araraquara Cerrado area, Sao Paulo state, Brazil.	Exhibit antifungal activity (244–245) Cytotoxicity (244)	[80]
244	C16H26O5	4
245
246	C9H12O2	4	amorphous powder	Xylaria curta 92092022	barks	Taiwan China	Show moderate antibacterial and phytotoxic activities	[81]
247	C16H22O5	6	white powder	Trichoderma sp. 307 & Acinetobacter johnsonii B2	Strain 307, stem bark of Clerodendrum inerme	Guangdong Province, China	Exhibit potent α-glucosidase inhibitory activity (247–248) show moderate inhibitory activity against α-glucosidase (249)	[10]
248	C16H20O5	7
249			colorless needles
250	C10H16O3	3	colorless oil	Pestalotiopsis sp.	fruits of Drepanocarpus lunatus (Fabaceae)			[12]
251	C13H18O5	5
252	C11H14O5	5	colorless crystals	Talaromyces sp.	Xanthoparmelia angustiphylla	Stockholm, Sweden	Exhibit selective cytotoxicities	[82]
253	C32H50O7	8	yellow powder	Mutant CS/asm21-4	Maytenus hookeri	China	Exhibit antibacterial activity	[83]
254	C22H21NO4	13	light yellow gum	Aspergillus terreus	Yongxing Island fresh, healthy leaves of S. maritima L.	South China Sea, China	Show strong inhibitory effects on the production of NO (256–257)	[84]
255	C22H19O4	14
256	C22H21NO5	13
257	C22H21NO5	13
258	C20H22O3	10	yellow oil	Aspergillus sp.	root of Tripterygium wilfordii	Wuhan, China	Exhibited weak AchE and BACE1 inhibitory activity (260–261) Showed excellent inhibitory effects on the production of IL-1β, TNF-α, and NO (258–261)	[85]
259	C24H26O6	12	yellow oil
260	C24H26O6	12	colorless oil
261	C23H26O6	11
262	C22H36O8	5	oil	H. fuscum	lichen Usnea sp.	Yunnan, China	Exhibit moderate cytotoxicity	[86]
263	C26H34O12	10	white powder	Talaromyces purpurogenus	fresh leaves of the toxic medicinal plant Tylophora ovata	China		[87]
264	C28H36O12	11
265	C26H40O9	7
266	C11H18O3	3	yellow oil	Penicillium coffeae MA-314	fresh inner tissue of the leaf of marine mangrove plant Laguncularia racemosa	Hainan island, China	Exhibit potent antifungal activity	[77]
267	C12H12O5	7	brown solids	Phomopsis sp.	stems of Isodon eriocalyx var. laxiflflora	Kunming, China		[43]
268	C17H14O3	11	white amorphous powder	Phyllosticta sp. J13-2-12Y	leaves of Acorus tatarinowii	Guangxi Province, China		[88]
269
270	C19H16O5	12	colorless oil
271	C16H12O3	11	colorless crystal
272	C22H26O6	10	luminous yellow oil	Pestalotiopsis microspora	fruits of Manilkara zapota	Kandy, Sri Lanka		[89]
Anthraquinones
273	C12H14O5	6	yellow amorphous powder.	Penicillium citrinum Salicorn 46	Salicornia herbacea Torr.	China		[90]
274	C14H14O4Cl2	7	yellow oil	Lachnum cf. pygmaeum DAOMC 250335	dead P. rubens twig	NB, Canada	Inhibit the growth of M. violaceum,	[58]
275	C16H12O6	11		Apiospora montagnei	lichen Cladonia sp.			[37]
276	C18H14O7	12	yellow crystal	Eurotium chevalieri KUFA 0006	healthy twig of Rhizophora mucronata Poir.	Chanthaburi Province, Eastern Thailand	Cause a significant reduction in biofilm production	[62]
277	C15H16O3	8		Nigrospora oryzae co-cultured with Irpex lacteus	seeds of Dendrobium offifficinale	Yunnan Province China		[14]
278	C15H18O2	7
279	C15H20O4	6
280	C15H20O6	6
281	C14H16O2	7		Phoma betae	Kalidium foliatum (Pall.)	China	Cytotoxic activities (281)	[91]
282	C14H16O3	7
283	C14H20O5	5
284	C27H24O10	16	red powder	Neofusicoccum austral SYSU-SKS024	branches of the mangrove plant Kandelia candel	Guangxi province, China	Show inhibitory effects against Indoleamine 2,3-dioxygenase (IDO)	[92]
285	C15H16O6	8	yellow powder
286	C14H18O5	6	white powder
287	C16H18O5	8	yellow amorphous powder	Nectria pseudotrichia 120-1NP	healthy stem of Gliricidia sepium	Yogyakarta, Indonesia	Exhibit antibacterial activity Exhibit cytotoxicity	[31]
288	C30H22O12	20	yellow powder	ARL-09 (Diaporthe sp.)	Anoectochilus roxburghii	China	Cytotoxicity Effects on NF-κB signaling pathway	[93]
289	C40H45NO10S	19	red powder	CS/asm21-4	callus of Chinese medicinal plant Maytenus hookeri	China	Show moderate antimicrobial activities (antibacterial activities and antifungal activity) (289–291)	[83]
290	C40H49NO12	17	yellow powder
291	C40H44NO8Cl	19
292	C12H18O6	4	colorless oil	Xylaria sp. SYPF 8246	root of Panax notoginseng	Yunnan, China		[94]
293	C15H14O6	9		Talaromyces funiculosus	lichen thallus of Diorygma hieroglyphicum	India	Display antimicrobial activity	[95]
294	C16H14O7	10	yellow gum	Simplicillium lanosoniveum Zare & W. Gams PSU-H168 and PSU-H261	leaves of Hevea brasiliensis	Songkhla Province, Thailand	Display antifungal activity	[96]
295	C17H18O7	9	red amorphous powder	Fusarium napiforme	mangrove plant, Rhizophora mucronata	Makassar, Indonesia	Exhibit moderate antibacterial activity (295–296) Phytotoxic (295–296)	[97]
296	C16H16O6	9	orange amorphous powder
Sterides
297	C34H52O8	9	faint yellow oil	Xylaria sp.	leaves of Panax notoginseng	Yunnan province China	Show cytotoxicity (297)	[98]
298	C28H44O7	7	semitransparent oil
299	C25H36O5	8	colorless needle	Chaetomium sp. M453	Chinese herbal medicine Huperzia serrata	Yunnan Province, China	Show weak acetylcholinesterase inhibitory activity (302)	[99]
300	C25H36O5	8	colorless amorphism
301	C25H34O5	9
302	C28H42O3	8	yellow oil
303	C22H32O3	7	colorless crystals	Stemphylium sp. AZGP4–2	root of Polyalthia laui	Hainan Province China	Show antibacterial activity against Escherichia coli (303) Exhibit antibacterial activity (304)	[100]
304	C23H36O3	6
305	C23H34O3	7	colorless needle crystals
306	C44H72O2	9	white amorphous powder	Fusarium sp.	Mentha longifolia L. (Labiatae) roots	Saudi Arabia	Possessed 5-LOX inhibitory potential (306–308)	[101]
307	C28H46O3	6
308	C30H48O5	7
309	C28H40O2	9	colorless powder	Pleosporales sp. F46 and Bacillus wiedmannii. Com1	medicinal plant Mahonia fortunei	Qingdao, China.	Exhibit moderate antibacterial efficacy	[102]
310	C32H41NO3	13	white power	Aspergillustubingensis YP-2	bark of Taxus yunnanensis	Yunnan Province, China	Show weak cytotoxicities (311)	[103]
311	C22H34O3	6
Other types of compounds
312	C21H24O6	10	colorless oil	Talaromyces stipitatus SK-4	leaves of a mangrove plant Acanthus ilicifolius	Guangxi Province, China	Show antibacterial activity and inhibitory against α-glucosidase (313)	[104]
313	C23H26O7	11
314	C15H21NO8	6	whitish needles	C. ninchukispora BCRC 31900	seeds of medicinal plant Beilschmiedia erythrophloia Hayata	Taiwan China	Show anti-inflammatory effects through inhibition of NO production (317,314–315)	[105]
315	C15H21NO7	6
316	C16H23NO7	6
317	C15H21NO8	6	yellowish solid
318	C15H16O5	8	white amorphous powder	Pyronema sp. (A2-1 & D1-2)	Taxus mairei	Hubei province, China	Exhibit moderate antibiotic activity	[106]
319	C11H16O4	4	yellow oil	Phoma sp. nov. LG0217	branches of Parkinsonia microphylla	Tucson, Arizona		[107]
320	C12H16O4	5	colorless amorphous powder	Penicillium citrinum Salicorn 46	Salicornia herbacea Torr	China	Exhibit potent cytotoxic activity	[90]
321	C21H29NO9	8	colorless gum	Phomopsis sp. PSU-H188	midrib of Hevea brasiliensis	Trang Province, Thailand		[108]
322	C20H28O7	7
323	C21H27O6N	9	yellow amorphous solid	Fusarium solani JK10	root of the Ghanaian medicinal plant Chlorophora regia	Eastern Region of Ghana	Exhibit antibacterial efficacies (325–326,328)	[109]
324
325	C21H27O7N	9
326
327	C21H25O8N	10
328	C22H29O7N	9	pale yellow amorphous solid
329	C22H29O5N	9	yellow amorphous solid
330	C14H14O4	8	colourless oil	Phomopsis longicolla HL-2232	fresh healthy leaf of Brguiera sexangula var. rhynchopetala	South China Sea	Show moderate antibacterial activities	[110]
331	C9H16O4	2	white needles	Penicillium sp. OC-4	leaves of Orchidantha chinensis	Guangdong Province, China	Display strong antioxidant activity	[111]
332	C16H24O6	5	colorless, amorphous solid	Curvularia sp.	leaf of the medicinal plant Murraya koenigii	Bangladesh	Exhibit zoospore motility impairment activity (333–334)	[112]
333	C12H18O6	4
334	C10H12O3	5	colorless crystals
335	C10H16O4	3	colorless oil
336	C20H16O5	13	yellow viscous oil	Rhytidhysteron rufulum AS21B	leaves of Azima armentosa	Samutsakhon province, Thailand	Display the most promising anti-tumor activity (337)	[113]
337	C22H18O5	14	pale yellow gum
338	C11H12O4	6	brown solids	Phomopsis sp. sh917	stems of Isodon eriocalyx var. laxiflora	Kunming, China		[43]
339	C15H15NO3	9	brown gum	Dendrothyrium variisporum	roots of the Algerian plant Globularia alypum	Algeria	Show the strongest activity against Bacillus subtilis and Micrococcus luteus (339)	[60]
340	C14H13NO2	9
341	C12H17NO3	5
342	C15H18N2O4	8	light yellow gum	Trichoderma atroviride	bulb of Lycoris radiata	china		[11]
343	C32H34N2O4	17	yellow crystal.	Penicillium chrysogenum V11	vein of Myoporum bontioides A. Gray	Leizhou Peninsula, China	Display significant antifungal activity and remarkable cytotoxicities	[114]
344	C14H15NO	8	yellow crystal	Eurotium chevalieri KUFA 0006	healthy twig of Rhizophora mucronata Poir.	Chanthaburi Province, Eastern Thailand	Show inhibition of biofilm production (344–345)	[62]
345	C14H15NO	8	yellowish viscous liquid
346	C13H15NO3	7
347	C18H18O6	10	colorless solid	Simplicillium sp. PSU-H41	leaf of Hevea brasiliensis (Euphorbiaceae)	Songkhla, Thailand	Display weak antibacterial against Staphylococcus aureus (347) Exhibit weak antifungal activity against Cryptococcus neoformans (349)	[63]
348	C19H20O6	10	pale yellow solid
349	C20H20O6	11
350	C25H24O7	14
351
352	C25H22O8	15	yellow gum
353	C24H26O7	12	pale yellow gum
354	C34H30O11	20	colorless solid
355	C31H28O8	18	pale yellow gum
356	C17H24N2O6	7	colorless viscous oil	Phoma herbarum PSU-H256	leaf of Hevea brasiliensis	Songkhla, Thailand		[115]
357	C12H13NO6	7
358	C16H19NO7	8
359	C15H17NO5	8
360	C7H12N2O3	3
361	C14H14N2O5	9
362	C11H12O3	6	white amorphous solid.	Penicillium sp.	leaf of Senecio flavus (Asteraceae)	Al-Azhar University Egypt	Show antifungal activity and cytotoxic activity	[116]
363	C30H37NO7	13	white amorphous powder	R. sanctae-cruciana	leaves of the medicinal plant A. lebbeck.	India	Show considerable cytotoxic potential	[117]
364	C24H30O4	10	yellowish oil	Arthrinium arundinis TE-3	fresh leaves of cultivated tobacco	Hubei Province China	Show selective antifungal activity (364–365) Display moderate in vitro cytotoxicity (365)	[118]
365	C20H24O4	9
366	C20H24O3	9
367	C23H24O5	12	brown powder	Aspergillus flavipes Y-62	stems of plant Suaeda glauca (Bunge) Bunge	Zhejiang province, East China	Show weak antimicrobial activity	[119]
368	C16H14O6	9	colorless crystals	Mycosphaerella sp. (UFMGCB2032)	healthy leaves of Eugenia bimarginata	Atlanta, GA, USA	Exhibit moderate antifungal activities	[120]
369	C17H18O9	9	colorless solid
370	C20H16O5	13	off-white gum	Anteaglonium sp. FL0768	Living photosynthetic tissue of sand spikemoss (Selaginella arenicola; Selaginellaceae)			[121]
371	C28H26N2O5	17	amorphous light yellow powder	Penicillium janthinellum SYPF 7899	three-year-old healthy P. notoginseng	Yunnan province, China	Exhibit significant inhibitory activities (371–373)	[122]
372
373	C15H19NO6	7	brown oil
374	C14H24O4	3	colorless oil	Phaeophleospora vochysiae sp. nov	Vochysia divergens	wetland in Brazil	Show considerable antimicrobial activity	[123]
375	C12H17NO6	5	colorless oil	Bionectria sp.	fresh seeds of R. teadigera	Haut Plateaux region, Cameroon		[70]
376	C18H14N2O6	13	white powder
377	C13H19NO4	5	yellowish oil	Trichoderma atroviride S361	bark of Cephalotaxus fortunei	Zhejiang province, China		[17]
378
379	C18H20O7	9	amorphous powder	Xylaria sp. SYPF 8246	root of Panax notoginseng	Wenshan, Yunnan, China	Display significant inhibitory activities against human carboxylesterase 2 (hCE 2) (379,383–385)	[94]
380	C12H10O5	8	colorless oil
381	C12H18O6	4
382	C12H20O5	3
383	C19H22O7	9
384	C19H21O7Cl	9
385	C18H19O7Cl	9
386	C32H42O4	12	brown oil	Byssochlamys spectabilis	leaf tissue of the medicinal plant Edgeworthia chrysantha	Zhejiang Province, China	weakly active against Escherichia coli and Staphyloccocus aureus (388) Display selective inhibitory effects toward hCE2-mediated FD hydrolysis (386)	[124]
387	C16H22O3	7	yellow oil
388	C16H26O2	5
389	C20H29N5O6	9	white amorphous powder	Fusarium chlamydosporium	Anvillea garcinii (Burm.f.) DC. leaves	Egypt	Exhibit selective antifungal activity and cytotoxic effect possess high antibacterial potential	[125]
390	C15H16N2O2	9		Annulohypoxylon stygium	red seaweed Bostrychia radicans	Ubatuba city, São Paulo State, Brazil		[126]
391	C23H16O2N2	17	purple-red powder	Alternaria alternata Shm-1	fresh wild body of Phellinus igniarius	Shanxi Province, China		[127]
392	C10H12O6	5	colorless crystals	Cladosporium sp. JS1–2	mangrove Ceriops tagal	Hainan Province in China	Show moderate antibacterial activities (392–393) Showed growth inhibition activities against newly hatched larvae of H. armigera Hubner (392–393)	[128]
393	C10H14N2O2	5	yellow powder
394	C8H13NO4	3	white solid	Diaporthe vochysiae sp. nov. (LGMF1583)	medicinal plant Vochysia divergens		Display considerable antibacterial activity (395) Show low to moderate cytotoxic activity (394–395)	[129]
395	C11H17NO4	4	white solid
396	C28H40O6	9	yellow oil	Diaporthe lithocarpus A740	Twigs of medicinal plant Morinda officinalis	Guangdong province , China	Show weak cytotoxic activity (396–397)	[41]
397	C28H40O6	9
398	C30H37O7N	13	colorless powder	Xylaria longipes		Ailao Moutain		[130]
399	C30H39O9N	12
400	C32H41O8N	13
401
402	C30H37NO7	13
403	C18H18O7	10		Penicillium citrinum	Parmotrema sp.	Hakgala montane forest in Sri Lanka	Show moderate antioxidant activity	[131]
404	C11H11ClO5	6		Periconia macrospinosa KT3863	a terrestrial herbaceous plant	Kanagawa prefecture, Japan		[132]
405	C12H13ClO4	6
406	C7H12O3	2	light yellow liquid	Lasiosdiplodia pseudotheobromae			Exhibite XO inhibition (407) oxidized form of 406 show high XO inhibition	[133]
407	C13H22O3	3
408	C17H16O8	10	pale-yellow needles	Pleosporales sp. SK7	leaves of the mangrove plant Kandelia candel	Guangxi Province, China		[23]
409	C15H19N2O2	8	faint yellow oil	Aspergillus sp. AV-2	inner healthy leaves of mangrove plant Avicennia marina	Hurghada, Egypt		[134]
410	C19H22O5	9	yellow powder
411	C10H14O3	4	yellowish oil	Irpex lacteus DR10-1	Roots of waterlogging tolerant plant Distylium chinense	Chongqing in the TGR area, China	Exhibit strong antioxidant activity (413) Show moderate antibacterial activity (411–413)	[24]
412	C10H14O3	4
413	C12H16O4	5	brown flaky solid
414	C33H50O6	9	pale yellow oil	Penicillium crustosum PRB-2 & Xylaria sp. HDN13-249	Xylaria sp. HDN13-249: root of Sonneratia caseolaris	Hainan province, China	Show antibacterial activity (415–416) Show promising activity against M. phlei (416)	[135]
415	C33H50O9S	9
416	C24H40O5	5	pale yellow oils	Xylaria sp. HDN13-249
417	C24H40O8S	5
418	C9H14O2	3	colorless oil	Aspergillus terreus EN-539 & Paecilomyces lilacinus EN-531	inner tissues of the marine red alga Laurencia okamurai	China	Exhibit inhibitory activity against bacteria and fungi	[136]
419	C23H20O5	14	white powder	Diaporthe lithocarpus	leaves of Artocarpus heterophyllus	Dortmund, Germany		[137]
420	C16H20N2O4	8	colourless oil	Aspergillus aculeatus F027	fresh leaves of Ophiopogon japonicus (Linn. f.) Ker-Gawl	Hubei province of China		[138]
421	C17H20O6	8	reddish oil	Fusarium solani B-18	inner tissue of the unidentifified forest litters	Mount Merapi area Sleman, Yogyakarta, Indonesia.	Activat a signaling pathway in osteoclastic differentiation of murine macrophage (421)	[139]
422	C17H20O6	8	yellow oil
423	C15H18O5	7	reddish oil
424	C15H18O5	7	pale-yellow oil
425	C16H20O5	7	amorphous powder	Hypoxylon fuscu	lichen Usnea sp.	Lilong Snow Mountain in Lijiang, Yunnan, China	Exhibit moderate cytotoxicity (426–427)	[86]
426	C21H36O6	4	white solid
427	C18H30O7	4	white powder
428	C18H28O6	5
429	C25H24O6	14	colorless gum	Simplicillium lanosoniveum (J.F.H. Beyma) Zare & W. Gams PSU-H168 and PSU-H261	leaves of Hevea brasiliensis	Songkhla Province, Thailand	Exhibit antibacterial activity (430) Display antifungal activity (430–431)	[96]
430	C32H34O8	16
431	C16H14O7	10	yellow gum
432	C14H20O4	5	white amorphous powder	Clonostachys rosea B5-2	mangrove plants	Garut, Indonesia	Exhibit phytotoxicity against lettuce seedlings (432)	[140]
433	C7H10O3	3	colourless oil
434	C9H12O3	4	white amorphous powder
435	C9H14O4	3
436	C26H32O12	11	white powder	Talaromyces purpurogenus	fresh leaves of the toxic medicinal plant Tylophora ovata	Guangxi Province, China	Show significant inhibitory activity against NO production in LPS-induced RAW264.7 cells (436) Show moderate inhibitory activities toward XOD and PTP1b (437,441)	[87]
437	C26H38O11	8	white powder
438	C27H28O8	14	white powders
439	C29H40O9	10
440	C27H40O7	8
441	C26H34O7	10
442	C22H32N4O5	9	white powder	Phomopsis sp. D15a2a	leaves of Alternanthera bettzickiana (Amaranthaceae)	Anambra state of Nigeria		[55]
443	C8H13NO5	3
444	C20H38O7	2	colorless oil	Aureobasidium pullulans AJF1	flower of Aconitum carmichaeli,	Jangbaek Mountain, Gangwon-do, Korea		[141]
445	C30H56O10	3
446	C16H14O8	10	yellow amorphous powder	Alternaria alternata JS0515	Vitex rotundifolia (beach vitex)	Suncheon, Korea		[142]
447	C23H27O5Cl	10	colorless oil	Armillaria sp. & Epicoccum sp. YUD17002	YUD17002: rhizomes of the underground portion of Gastrodia elata	Yunnan Province, China	Exhibit moderate in vitro cytotoxic activities (447) Show weak acetylcholinesterase Inhibitory activity (447)	[27]
448	C10H10O4	6	white amorphous powder
449	C14H20O9	5	light-yellow oil

Author Contributions

C.Z. was responsible for the ideation of the whole article; R.Z. performed the review writing, data collection and data analysis, as well as post-revision work; S.L. contributed to determine the title of the review and made suggestions for the revision of the review; X.Z. helped to revise and proofread the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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