Potential of Secondary Metabolites of Diaporthe Species Associated with Terrestrial and Marine Origins

Abstract

Diaporthe species produce versatile secondary metabolites (SMs), including terpenoids, fatty acids, polyketides, steroids, and alkaloids. These structurally diverse SMs exhibit a wide range of biological activities, including cytotoxic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, and phytotoxic activities, which could be exploited in the medical, agricultural, and other modern industries. This review comprehensively covers the production and biological potencies of isolated natural products from the genus Diaporthe associated with terrestrial and marine origins. A total of 275 SMs have been summarized from terrestrial (153; 55%) and marine (110; 41%) origins during the last twelve years, and 12 (4%) compounds are common to both environments. All secondary metabolites are categorized predominantly on the basis of their bioactivities (cytotoxic, antibacterial, antifungal, and miscellaneous activity). Overall, 134 bioactive compounds were isolated from terrestrial (92; 55%) and marine (42; 34%) origins, but about half the compounds did not report any kind of activity. The antiSMASH results suggested that Diaporthe strains are capable of encoding a wide range of SMs and have tremendous biosynthetic potential for new SMs. This study will be useful for future research on drug discovery from terrestrial and marine natural products.

1. Introduction

Diaporthe is an important fungal genus of plant pathogens [1] belonging to the family Diaporthaceae, order Diaporthales, and class Sordariomycetes [2]. It is isolated mainly from plant hosts, which are distributed worldwide; many of them have been reported as plant pathogens, nonpathogenic endophytes, or saprobes, and human and other mammalian pathogens [3,4]. Diaporthe sp. is a widespread fungal genus that colonizes a wide range of hosts. It consists of nearly 800 described species, with around 950 species being attributed to its asexual state (Phomopsis) [5]. It is often isolated from above-ground plants, especially tropical and temperate woody plants [6]. Among numerous endophytic fungi, the genus Diaporthe is known for its potent biosynthetic ability to produce bioactive metabolites [7,8]. Secondary metabolites (SMs) isolated from Diaporthe sp. have shown a wide range of biological activities and chemical structures [9,10]. Chemical studies on some Diaporthe spp. have revealed a variety of bioactive natural products [11], such as cytotoxic diapolic acids [12], antifungal compounds [5,13], antibacterial agents [14,15], anti-candidal ketone derivatives [16], and anti-tubercular metabolites [17]. In the last twelve years, a total of 106 bioactive SMs have been reported from the genus Diaporthe [18].

Endophytic communities that develop inside the host plants are influenced by various parameters, such as environmental conditions (terrestrial and marine), host type, etc. [19]. Fungal endophytes are asymptomatic inhabitants of plant tissues that have the capability to colonize all parts of plants and determine their functional aspects, including increasing plant growth, acting as a biocontrol agent, naturally protecting the host from pests, and enduring tolerance against numerous biotic/abiotic stresses [20,21]. In return, they benefit from host plants in several ways, including providing nutrients, protection from desiccation, spatial structure, and passing on reproductive fungal propagules to the next generation of hosts in the case of vertical transmission [22]. Due to the vast diversity of endophytic fungal communities, the characterization of the SMs of each endophytic fungal community is difficult; therefore, the current review aims to describe the SMs species from the genus Diaporthe from two main origins (terrestrial and marine) and, furthermore, to classify them on the basis of their biological potency.

2. Terrestrial Origin

2.1. Cytotoxic Metabolites

Liu et al. (2013) isolated nine compounds (1–9), including a novel (1R,2E,4S,5R)-1-[(2R)-5-oxotetrahydrofuran-2-yl]-4,5-dihydroxy-hex-2-en-1-yl(2E)-2 methylbut-2-enoate (1), a known (1R,2R,4R)-trihydroxy-p-menthane (2), three linear furanopolyketides (3–5), and four lovastatin analogues, oblongolides D (6), H (7), P (8), and V (9), from Diaporthe sp. SXZ-19 on C. acuminate. These compounds showed weak cytotoxic activities against HCT 116 cells at a concentration of 10 µM [23]. Two bioactive metabolites, emodin (10) and arbutin (11), were isolated from an endophytic fungus D. lithocarpus. Compound 10 exhibited remarkable cytotoxic activity against P-388 murine leukemia cells (IC₅₀ = 0.41 µg/mL), and 11 showed moderate cytotoxicity against murine leukemia P-388 cells and had an IC₅₀ value at 2.91 µg/mL [15]. Two cytoskyrin-type bisanthraquinones, cytoskyrin C (12), and (+)-epicytoskyrin (13), were isolated from Diaporthe sp., an endophytic fungus derived from Anoectochilus roxburghii. Both compounds showed dose-dependent cytotoxicities against SMMC-7721 cells [24]. A new compound, vochysiamide B (14), and the known 2,5-dihydroxybenzyl alcohol (15) were derived from D. vochysiae LGMF1583 on the medicinal plant Vochysia divergens and showed cytotoxic activities against A549 human non-small cell lung and PC3 human prostate cell lines [8]. Mycoepoxydiene (16) and eremofortin F (17) were obtained from the endophytic fungus Diaporthe sp. SNB-GSS10 on Sabicea cinerea and showed cytotoxic activity against KB and MRC5 cells [6].

Two eremophilanes, lithocarins B (18) and C (19), were isolated from an endophytic fungus D. lithocarpus A740 on Morinda officinalis. Both compounds exhibited cytotoxicity against SF-268, MCF-7, HepG-2, and A549 tumor cells with IC₅₀ values between 37.68 and 97.71 µM [9]. The endophytic fungus D. terebinthifolii GG3F6, derived from the medicinal plant Glycyrrhiza glabra, was a source of the metabolite xylarolide (20), which showed cytotoxicity against MIAPaCa-2, HCT-116, and T47D cancer cells with IC₅₀ values of 38 µM, 100 µM, and 7 μM, respectively [12]. The metabolites xylarolide A (21) and xylarolide (20) were isolated from the fungus Diaporthe sp. on D. inoxia and showed remarkable cytotoxicity against MIAPaCa-2 with IC₅₀ values of 20 μM and 32 μM, respectively, and against PC-3 with IC₅₀ values of 14 μM and 18 μM, respectively [25]. Brissow et al. (2017) obtained 18-des-hydroxy cytochalasin H (22) from the endophytic fungus D. phaseolorum-92C on Combretum lanceolatum. This compound exhibited cytotoxic activity against the breast cancer cells MDA-MB-231 and MCF-7 [26]. A new brasilane-type sesquiterpenoid, diaporol R (23), was isolated from an endophytic Diaporthe sp. on leaves of R. stylosa. Diaporol R had a moderate cytotoxic effect on SW480 cancer cells and exhibited an IC₅₀ value of 8.72 ± 1.32 µM [27]. Diaporone A (24), a new dihydroisocoumarin derivative, was isolated from the crude extract of the plant endophytic fungus Diaporthe sp. and exhibited weak cytotoxicity against the human cervical cancer (HeLa) cell line with an IC₅₀ value of 97.4 μM [28]. Yang et al. (2020) isolated nine cytochalasans (25–33) from the endophytic fungus Diaporthe sp. SC-J0138 isolated from the leaves of Cyclosorus parasiticus. All compounds showed cytotoxic activity [29]. Khan et al. (2023) isolated a novel compound phomopthane A (34) from the plant-derived fungus D. unshiuensis YSP3, which exhibited cytotoxic activities against HeLa and MCF-7 cells with IC₅₀ values of 5.92 µM and 7.50 µM, respectively [30]. Compounds 1–34 are shown in Figure 1.

2.2. Antibacterial Metabolites

Two isocoumarin metabolites, (10S)-diaporthin (35) and orthosporin (36), were isolated from D. terebinthifolii LGMF907 isolated from Schinus terebinthifolius. They showed antibacterial activities against methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus [31]. A new 3-substituted-5-diazenylcyclopentendione, named kongiidiazadione (37), was separated from D. kongii on C. lanatus and showed antibacterial activity against Bacillus amyloliquefaciens [32]. The three metabolites emodin (10), coumarin (38), and 1,2,8-trihydroxyanthraquinone (39) were isolated from the endophytic fungus D. lithocarpus. Compound 38 had a diameter inhibition zone of 12.3 ± 0.3 mm against the bacterium B. subtilis, and 10 showed antibacterial activity against B. subtilis, M. luteus, Pseudomonas fluorescences, E. coli, and S. cerevisiae with inhibition zone diameters of 14.7 mm, 13.2 mm, 13.7 mm, 12.7 mm, and 11.7 mm, respectively, while compound 39 displayed antibacterial activity against B. subtilis, E. coli, and S. cerevisiae with inhibition zone diameters of 14.2 mm, 11.3 mm, and 10.7 mm, respectively [15]. Two antibacterial metabolites, phomosines A (40) and C (41), were extracted from Diaporthe sp. F2934 of the plant Siparuna gesnerioides. Both were active against S. aureus, M. luteus, Streptococcus oralis, Enterococcus fecalis, Enterococcus cloacae, and Bordetella bronchiseptica, with the diameter of the zone of inhibition ranging from 6 ± 0.62 to 12 ± 1.18 mm at a concentration of 4 µg/µL [11].

A new lanostanoid, 19-nor-lanosta-5(10),6,8,24-tetraene- 1α,3β,12β,22S-tetraol (42), along with two known steroids, 3b,5a,9a-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (43) and chaxine C (44), were isolated from Diaporthe sp. LG23 on the Chinese medicinal plant Mahonia fortune. Compound 42 exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria, and 43 and 44 showed antibacterial activity against B. subtilis with streptomycin as a positive control [14]. Two new fatty acids, diapolic acids A and B (45 and 46), along with two known compounds, xylarolide (20) and phomolide G (47), were isolated from the endophytic fungus D. terebinthifolii GG3F6, which was derived from the medicinal plant Glycyrrhiza glabra. All these compounds show antibacterial activity against Y. enterocolitica with IC₅₀ values of 78.4 μM, 73.4 μM, 72.1 μM, and 69.2 μM, respectively [12]. The new 21-acetoxycytochalasins J₃ (48) was extracted from Diaporthe sp. GDG-118 on Sophora tonkinensis and showed moderate antibacterial activity against Bacillus anthraci and Escherichia coli [33]. A carboxamide, vochysiamide B (14), from D. vochysiae LGMF1583 showed antibacterial activity on the Gram-negative bacterium Klebsiella pneumoniae (KPC) with a minimum inhibitory concentration (MIC) value of 80 μg/mL [8]. Flavomannin-6,60-di-O-methyl ether (49) was extracted from an endophytic strain of D. melonis from Annona squamosal, which showed antimicrobial activity against S. aureus 25697, S. aureus 29213, and Streptococcus pneumonia ATCC 49619 with MIC values of 32 μg/mL, 32 μg/mL, and 2 µg/mL, respectively [34]. A phenolicmetabolite, tyrosol (50), was extracted from D. helianthi isolated from Luehea divaricate. Tyrosol showed significant antagonistic activity against several tested pathogenic bacterial strains [35]. Compound 24 was isolated from the plant endophytic fungus Diaporthe sp. and showed moderate antibacterial activity against Bacillus subtilis with a MIC value of 66.7 μM [28]. The novel 3-methoxy-5-methylnaphthalene-1, 7-diol (51) was isolated from a Diaporthe sp. on the plant Syzygium cordatum. Compound 51 demonstrated antibacterial activity against Pseudomonas syringae pv phaseolicola and Xanthomonas axonopodis pv phaseoli, with MIC values of 2.50 mg/mL (7.00 ± 0.00 mm) and 1.25 mg/mL (7.67 ± 0.33 mm), respectively, against test organisms [36]. A new alternariol methyl ether-12-O-α-D-arabinoside (52) derived from D. unshiuensis YSP3 and showed antibacterial effect on B. subtilis (MIC value 16 μg/mL) [30]. The structures of compounds 35–52 are shown in Figure 2.

2.3. Antifungal Secondary Metabolites

Tanney et al. (2016) isolated four secondary metabolites of D. maritima from healthy Picea mariana and Picea rubens needles, including phomopsolides A (53), B (54), and C (55) and a stable a-pyrone, (S,E)-6-(4-hydroxy-3-oxopent-1-en-1-yl)-2H-pyran-2-one (56). All compounds showed antifungal activities against M. violaceum and Saccharomyces cerevisiae [5]. A known product, 7-hydroxy-6-metoxycoumarin (57), was isolated from the endophytic fungus D. lithocarpus, showing significant antifungal activity against Sporobolomyces salminocolor with an inhibition zone of 12.2 ± 0.3 mm [15]. A bis-anthraquinone derivative, (+)-2,20-epi-cytoskyrin A (58), was isolated from Diaporthe sp. GNBP-10 from Uncaria gambir Roxb. It showed antifungal activity against 22 yeast strains and 3 filamentous fungi with MICs ranging from 16 μg/mL to 128 µg/mL [37]. Cytochalasins were isolated from Diaporthe sp. GDG-118, including 7-acetoxycytochalasin H (59) and cytochalasins H (60) and E (61), and showed varying degrees of antifungal activity against Alternaria oleracea, Pestalotiopsis theae, Colletotrichum capsici, and Ceratocystis paradoxa [33]. The novel metabolite 3-hydroxy-5-methoxyhex-5-ene-2,4-dione (62) was isolated from Diaporthe sp. ED2 on the herb Orthosiphon stamieus Benth. It showed antifungal activity against C. albicans with an MIC value of 3.1 μg/mL [16]. A new metabolite, eucalyptacid A (63), along with the three known metabolites cytosporone C (64), 1-(4-hydroxyphenyl) ethane-1,2-diol (65), and (2-hydroxy-2-phenylethyl) acetamide (66), was isolated from the solid rice cultures of the endophytic fungus D. eucalyptorum KY-9 that had been isolated from Melia azedarach. All compounds exhibited antifungal activities against Alternaria solani [13]. Compounds 53–66 are shown in Figure 3.

2.4. Miscellaneous Activities

Seven metabolites, mucorisocoumarin A (67); pestalotiopsone B (68); acetoxydothiorelone B (69); dothiorelones B (70), L (71), and G (72); and cytosporone D (73), were isolated from the endophytic fungus D. pseudomangiferaea on Tylophora ouata. Compounds 67–73 displayed anti-fibrosis activity with inhibition rates of 17.4%, 59.2%, 62.9%, 41.1%, 32.9%, and 52.1% in human lung fibroblast MRC-5 cell activation induced by TFG-b at 10 µM. Cytosporone D (73) showed antioxidant activity with an inhibition rate of 63.3% by releasing MOA at a concentration of 10 µM and moderate antidiabetic activity toward protein tyrosine phosphatase 1B (PTP1B) [38]. The fungus D. eres derived from pathogen-infected leaves of Hedera helix produced an isocoumarin, 3,4-dihydro-8-hydroxy-3,5-dimethylisocoumarin (74), and tyrosol (50), which had a phytotoxic effect on the growth of Lemna paucicostata [39]. A novel metabolite, diportharine A (75), was obtained from the culture of a Diaporthe sp. isolated from Datura inoxia. It showed remarkable antioxidant activity by scavenging DPPH radicals (EC₅₀ = 10.3 µM) [25]. Two new benzopyranones, diaportheones A (76) and B (77), were extracted from Diaporthe sp. P133 from Pandanus amaryllifolius. They exhibited moderate antitubercular activities and achieved MIC values of 100.9 μM and 3.5 µM, respectively, against Mycobacterium tuberculosis H37Rv with rifampin as the positive control (MIC = 0.25 µM) [40]. The cyclohexeneoxidedione derivatives phyllostine acetate (78) and phyllostine (79) were extracted from D. miriciae on the plant Cyperus iria and showed potent antifeedant activities on Plutella xylostella. [41]. Cytoskyrin C (12) and (+)-epicytoskyrin (13) were isolated from Diaporthe sp. and were able to activate the NF-_KB pathway and increase the relative activity of luciferase at a concentration of 50 µM [24]. Five phytotoxic compounds, p-cresol (80), 4-hydroxybenzoic acid (81), 4-hydroxybenzaldehyde (82), nectriapyrone (83), and tyrosol (50), were isolated from D. eres on V. vinifera wood. In leaf disk and leaf absorption bioassays, the phytotoxicities of all compounds increased with concentration over the range 0.1–1 mg/mL [42]. Two diphenyl ether derivatives, diaporthols A (84) and B (85), were extracted from Diaporthe sp. ECN-137 isolated from the leaves of Phellodendron amurense. Compounds displayed a migration inhibitory effect on TGF-β1-triggered MDA-MB-231 breast cancer cells at a concentration of 20 µM [43]. Two new metabolites, gulypyrone A (86) and phomentrioloxin B (87), were extracted from a strain of D. gulyae isolated from C. lanatus, which had a low phytotoxic effect and caused some necrosis in various weed and crop species [44]. Phomolide C (88) from a Diaporthe sp. on Aucuba japonica var. borealis inhibited the proliferation of human colon adenocarcinoma cells at a concentration of 50 μg/mL [45]. Compound 18-des-hydroxy cytochalasin H (22) from the endophytic fungus D. phaseolorum-92C inhibited leishmanicidal activity and moderate antioxidant activity against the breast cancer cells MDA-MB-231 and MCF-7 [26]. Studies of the strain Diaporthe sp. JC-J7 from the stems of Dendrobium nobile led to the isolation of a new compound, diaporthsin E (89). It showed low antihyperlipidemic activity on triglycerides (TG) in steatotic L-02 cells with an inhibition rate of 26% at a concentration of 5 μg/mL [46]. Two dibenzopyrones, 2-hydroxy-alternariol (90) and alternariol (91), were isolated from the endophytic fungus Diaporthe sp. CB10100. Both compounds significantly reduced the production of NO to as low as 10 μM in LPS-induced RAW264.7 cells [47]. A new metabolite, phomentrioloxin (92), was isolated from the liquid culture of Phomopsis sp. (asexual state of Diaphorte), which showed phytotoxic activity, and caused growth and chlorophyll content reduction in fronds of Lemna minor and inhibition of tomato rootlet elongation [48]. Structures of compounds 67–92 are shown in Figure 4.

2.5. Compounds with No Activity

Two known compounds (93–94) isolated from D. lithocarpus showed no activity [15]. The compound vochysiamides A (95) from D. vochysiae LGMF1583 did not report activity [8]. The endophytic fungus D. pseudomangiferae yielded the inactive compound altiloxin A (96) [6]. A new benzophenone derivative, named tenllone I (97), the new lithocarin D (98), and the known phomopene (99) were isolated from the endophytic fungus D. lithocarpus A740. These compounds were not found to be significantly active [9]. Xylarolide B (100) isolated from the culture of an endophytic fungus Diaporthe sp. Harbored from Datura inoxia showed no activity [25]. Nine new sesquiterpenoids, diaporols J–Q and S (101–108 and 109), were isolated from Diaporthe sp., an endophytic fungus. None of them reported any activity [27]. Alternariol 4,10-dimethyl ether (110) and alternariol 4-methyl ether (111) were isolated from a crude extract of the plant endophytic fungus Diaporthe sp. and did not display any kind of bioactivity [28]. Three compounds, 4H-1-benzopyra-4-one-2,3-dihydro-5-hydroxy-2,8-dimetyl (112), 4H-1-benzopyran-4-one-2,3-dihydro-5-hydroxy-8-(hydroxy-lmethyl)-2-methyl (113), and phomosine D (114), were isolated from the Diaporthe sp. F2934. These isolated compounds were found to be inactive [11]. Four known compounds, 3β,5α,9α,14α-tetrahydroxy-(22E,24R)-ergosta-7,22-dien 6-one (115), (22E,24R)-ergosta-7,9(11),22-triene-3β,5α,6α-triol (116), demethylincisterol A3 (117), and volemolide (118), were isolated from an endophytic fungus, Diaporthe sp. LG23, and were found to have no bioactivity [14]. A chemical investigation into the endophyte D. melonis reported the isolation of two new compounds, diaporthemins A (119) and B (120). Neither compound was reported to have any kind of potency [34]. Three inactive metabolites, a new metabolite, eucalactam B (121), and two known metabolites, eugenitol (122) and 4-hydroxyphenethyl alcohol (123), were isolated from the solid rice cultures of the endophytic fungus D. eucalyptorum KY-9 [13]. The chemical exploration of an endophytic fungus D. pseudomangiferaea led to the isolation of eleven inactive (124–134) secondary metabolites [38]. Nine compounds (135–143) were isolated from a strain of D. gulyae, but did not report any bioactivity [44]. Ten inactive polyketones (144–153) were isolated from the fermentation of Diaporthe sp. JC-J7 [46]. Nine inactive metabolites (154–162) were isolated from the endophytic fungus Diaporthe sp. CB10100 [47]. An inactive new cytochalasan (163) was isolated from the endophytic fungus Diaporthe sp. SC-J0138 [29]. Two inactive novel compounds, phomopthane B (164) and phomopyrone B (165), were isolated from D. unshiuensis [30]. The structures of compounds 93–165 are shown in Figure 5.

3. Marine Origin

3.1. Antibacterial and Antifungal Metabolites

A chemical investigation into Diaporthe amygdali SgKB4, an endophytic fungal strain isolated from the West Sumatran mangrove plant Sonneratiagriffithii Kurz, led to the isolation of cytochalasin H (60). This compound showed mild antibacterial activity against some pathogenic bacteria [49]. The fungus D. phaseolorum derived from Laguncularia racemose, afforded 3-hydroxypropionic acid (166), which showed antimicrobial activity against S. aureus and S. typhi [50]. A new compound (167), named diaporthelactone, was isolated from the culture of Diaporthe sp., a marine fungus growing in the submerged decayed leaves of Kandelia candel in the mangrove, and exhibited inhibitory antifungal activity against Aspergillus niger with a MIC of 50 µg/mL [51]. Niaz et al. (2021) isolated a new isochromophilone G (168) along with six known azaphilones (169–174) from the endophytic fungus Diaporthe perseae on the Chinese mangrove Pongamia pinnata (L.). All compounds exhibited antibacterial potency against human pathogens [52]. Compounds 166–174 are shown in Figure 6.

3.2. Miscellaneous Activities

Three compounds, pestalotiopsones F (175) and B (176), and 3,8-dihydroxy-6-methyl-9-oxo-9Hxanthene- 1-carboxylate (177), were isolated from Diaporthe sp. SCSIO 41011. These compounds showed significant anti-IAV activities against three influenza A virus subtypes, including A/Puerto Rico/8/34 H274Y (H1N1), A/FM-1/1/47 (H1N1), and A/Aichi/2/68 (H3N2) [53]. Phomoxanthone A (178), with a novel carbon skeleton, was isolated from the fungus D. phaseolorum FS431 and showed good cytotoxic potency against MCF-7, HepG-2, and A549 with IC₅₀ values of 2.60 μM, 2.55 μM, and 4.64 µM, respectively [54]. A new compound biatriosporin N (179), together with five known compounds (180–182, 60, and 178), was obtained from the culture of the fungus Diaporthe sp. GZU-1021. All compounds displayed significant inhibitory effects against NO production with IC₅₀ values from 1.94 μM to 16.5 μM [55]. Six bioactive metabolites were separated from D. phaseolorum SKS019 derived from the mangrove plant A. ilicifolius, (−)-phomopsichin A (183), (+)-phomopsichin A (184), (+)-phomopsichin B (185), (−)-phomopsichin B (181), and the new diaporchromanones C (186) and D (187). These metabolites showed moderate inhibition of osteoclastogenesis by inhibiting RANKL-induced NF-_KB activation [56]. The fungus Diaporthe sp. SCSIO 41011, derived from the mangrove plant R. stylosa, yielded two metabolites, epi-isochromophilone II (172) and isochromophilone D (188). Compound 172 displayed cytotoxicity against ACHN, OS-RC-2, and 786-cells with IC₅₀ values of between 3.0 μM and 4.4 µM, and 188 had an IC₅₀ of 8.9 µM against 786-O cancer cells [57]. Compound 167 showed inhibitory activity against human tumor cell lines KB and Raji with IC₅₀ values of 6.25 μg/mL and 5.51 µg/mL, respectively [51]. Diaporisoindole A (189) and tenellone C (190) were obtained from Diaporthe sp. SYSU-HQ3 on the mangrove plant E. agallocha and displayed inhibitory activity on M. tuberculosis protein tyrosine phosphatase B (MptpB) (IC₅₀ values = 4.2 μM and 5.2 µM, respectively) [58]. Eight new compounds, diaporindenes A−D (191−194), isoprenylisobenzofuran A (195), diaporisoindoles D and E (196 and 197), and tenellone D (198), were isolated from the endophytic fungus Diaporthe sp. SYSU-HQ3 derived from the branches of Excoecaria agallocha. All metabolites displayed significant anti-inflammatory activity [59]. Cordysinin A (199) was derived from the endophytic fungus D. arecae on Kandelia obovate. It displayed antiangiogenic activity against human endothelial progenitor cells (EPCs) with an IC₅₀ value of 15.1 ± 0.2 μg/mL [60]. The metabolites 5-deoxybostrycoidin (200) and fusaristatin A (201) were obtained from D. phaseolorum SKS019 on the mangrove plant A. ilicifolius. Compound 200 showed cytotoxic activity against MDA-MB-435 and NCI-H460 with IC₅₀ values of 5.32 μM and 6.57 μM, respectively, and the IC₅₀ value of 201 on MDA-MB-435 was 8.15 μM [61]. Phomopsin F (202) was isolated from D. toxica and showed cytotoxic activity against HepG2 cells [62]. Two novel metabolites, longidiacid A (203) and longichalasin B (204), were isolated from the deep-sea-derived fungus Diaporthe longicolla FS429. These compounds were shown to inhibit 35.4% and 53.3% of the enzyme activity of the Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB), respectively, at a concentration of 50 µM [63]. The new diaporpenoid A (205) and the new diaporpyrone A (206) were isolated from a MeOH extract obtained from cultures of the endophytic mangrove fungus Diaporthe sp. QYM12. Compounds 205 and 206 exhibited potent anti-inflammatory activities by inhibiting the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells with IC₅₀ values of 21.5 μM and 12.5 µM, respectively [64]. Seven compounds (168–174) were isolated from the endophytic fungus D. perseae. Outstanding DPPH and ABTS radical scavenging activities were exhibited by all seven compounds [52]. Compounds 175–206 are shown in Figure 7.

3.3. Inactive Compounds

Secondary metabolites 207–221 and 124–134 were isolated from the mangrove-associated fungus Diaporthe sp. SCSIO 41011. None of these compounds reported any kind of activity [53]. Two new polyketides, phaseolorins G and H (222 and 223), and one new phaseolorin I (224), along with two known compounds (225 and 226), were isolated from D. phaseolorum FS431. None of these compounds showed any activity [54]. Two new metabolites, diaporchromanones A and B (227 and 228), and a known compound (229) were obtained from D. phaseolorum SKS019, but showed no activity [56]. Three chloroazaphilone derivatives (230−232) were obtained from the fungus Diaporthe sp. SCSIO 41011, along with three known analogues (233−235). None of these isolated compounds were reported to have any kind of activity [57]. Two inactive compounds, diaporisoindole B (236) and diaporisoindole C (237), were isolated from the endophytic fungus Diaporthe sp. SYSUHQ3 [58]. A new arecine (238) and twenty-two known diketopiperazines (239–260) were isolated from the endophytic fungus D. arecae, but showed no activity [60]. Six new compounds, including diaporphasines A–D (261–264) and meyeroguillines C and D (265–266), and a known meyeroguilline A (267) were isolated from an endophytic fungus D. phaseolorum. None of these compounds reported any kind of activity [61]. A chemical investigation into the fungus D. longicolla FS429 led to the isolation of six metabolites, the novel longidiacid B (268), two new polyketides (269–270), a new cytochalasin analogue longichalasins A (272), and two known compounds (271 and 273). None of them showed activity [63]. Four inactive compounds, including the new diaporpenoids B and C (274 and 275), and the known diaporpyrones B and C (160 and 161), were isolated from the mangrove endophytic fungus Diaporthe sp. QYM12 [64]. The structures of compounds 207–275 are shown in Figure 8.

In this paper, a total of 275 secondary compounds from the genus Diaporthe are summarized. As can be seen in Figure 9, 153 secondary metabolites were isolated from terrestrial origins and 110 from marine origins, and 12 were common to both environments. These compounds are categorized on the basis of their activity and inactivity. Figure 10 and Figure 11, and Table 1 and Table 2 show that about half of all 275 compounds reported from terrestrial and marine origins were inactive, accounting for 74 (45%) and 80 (66%) metabolites, respectively. Moreover, the active compound ratios were 56% and 34%, respectively. The active secondary metabolites showed various types of bioactivities, mainly cytotoxic (34; 20%), antibacterial (18; 11%), antifungal (14; 9%), and miscellaneous activities (26; 15%) for those of terrestrial origin and antibacterial and antifungal (10; 8%) and miscellaneous activities (32; 26%) for those of marine origin.

4. Analysis of Secondary Metabolite Biosynthetic Potential

Despite the numerous compounds isolated from Diaporthe species, recent advances in genome sequencing and bioinformatics analysis indicate that the number of biosynthetic gene clusters (BGCs) of SMs exceeds the number of SMs identified so far [65]. To fully understand SMs’ biosynthetic potential, we used the “antibiotics and secondary metabolite analysis shell–antiSMASH” tool to predict BGCs from the genomes of Diaporthe species available in the NCBI database (National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/, accessed on 1 February 2023). A total of 19 species were analyzed, and the antiSMASH 7 beta was applied using the “relaxed” detection strictness. As is shown in Figure 12, most species encoded ~90 BGCs to 110 BGCs except for Diaporthe aspalathi (46 BGCs) and Diaporthe helianthi (65 BGCs).

The BGCs were characterized as polyketide (PKSs), non-ribosomal peptides (NRPSs), terpenes, hybrid PKS-NRPSs, ribosomally synthesized and post-translationally modified peptides (RiPPs), and indole-related compounds. PKSs and NRPSs are the most abundant BGCs of all species (Figure 12). Some BGCs show high similarity with known BGCs, and their SMs are common to different species (Figure 13). A number of Diaporthe species were predicted to synthesize alternariol, mellein, and nectriapyrone C, which were noted for their phytotoxic and antimicrobial activities [66,67,68]. These metabolites may allow organisms to inhibit competitors that occupy the same niches and facilitate invasion when organisms are acting as phytopathogens. The BGCs of enniatin, ochratoxin A, and culmorin are present in several Diaporthe genomes [69,70,71]. These compounds are described as “emerging mytotoxins” and are mainly produced by the Fusarium species, which are wheat pathogens. This indicates that not only the Fusarium, but also the Diaporthe strains can produce contaminants in food and feed. Certain compounds with medicinal potential were also observed. Clavaric acid is an inhibitor of FPTase and may be effective as an anticancer agent in tumors [72]. FR901512 is an HMG-CoA reductase inhibitor that has the potential to lower cholesterol and fat [73].

5. Conclusions

This review highlights the potential of the secondary metabolites of the genus Diaporthe. A total of 275 secondary metabolites associated with terrestrial and marine environments have been isolated from this genus during the last twelve years. We can see in Figure 9 that of the 275 compounds reported, 153 (accounting for about 55% of the total) and 110 (about 41% of the total) were derived from terrestrial and marine origins, respectively, and 12 (about 4%) were isolated in both environments. After the comprehensive literature review, we found that active metabolites (56% and 34%, respectively) are less common than inactive metabolites (45% and 66%, respectively) in terrestrial and marine environments. Moreover, a total of 92 bioactive compounds (approximately 56%) were found in terrestrial samples, while 42 (about 34%) were found in marine samples. Current studies suggest that compounds with strong bioactivities could be used as potential drug candidates in the future, but more in-depth studies are needed to explore the mechanisms involved. This study also confirms the potential of terrestrial habitats for drug discovery and will help researchers find novel natural, potent fungal products. Genomic analyses suggested that Diaporthe species have great potential to produce more SMs. Therefore, future efforts should be focused on activating these silent BGCs via various methods, such as changing fermentation conditions, transcriptional regulation, using chemical elicitors, and heterologous gene expression.

Author Contributions

Investigation and data curation, W.W., B.K., Q.D., J.L., L.K. and N.A.R.; writing—review and editing, W.W., B.K., W.Y. and G.L. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures and Tables

Figure 1. Chemical structures of compounds 1–34 of terrestrial origin.

Figure 2. Chemical structures of compounds 35–52 of terrestrial origin.

Figure 3. Chemical structures of compounds 53–66 of terrestrial origin.

Figure 4. Chemical structures of compounds 67–92 of terrestrial origin.

Figure 5. Chemical structures of compounds 93–165 of terrestrial origin.

Figure 6. Chemical structures of compounds 166–174 of marine origin.

Figure 7. Chemical structures of compounds 175–206 of marine origin.

Figure 8. Chemical structures of compounds 207–275 of marine origin.

Figure 9. Total number of compounds isolated from genus Diaporthe.

Figure 10. The proportion of secondary metabolites of terrestrial origin.

Figure 11. The proportion of secondary metabolites of marine origin.

Figure 12. The number (y-axis) and type of secondary-metabolite BGCs in Diaporthe strains deposited in the NCBI database.

Figure 13. Some secondary compounds produced by species of Diaporthe that are 100% identical to known BGCs.

Table 1

Secondary metabolites associated with terrestrial origin.

No.	Compound	Producing Strain	Active/Inactive	Ref.
1	(1R,2E,4S,5R)-1-[(2R)-5-oxotetrahydrofuran-2-yl]-4,5-dihydroxy-hex-2-en-1-yl(2E)-2 methylbut-2-enoate	Diaporthe sp. SXZ-19	Cytotoxic	[23]
2	(1R,2R,4R)-trihydroxy-p-menthane	−	Cytotoxic	−
3	butyl 5-[(1R)-1-hydroxyethyl]-γ-oxofuran-2-butanoate	−	Cytotoxic	−
4	3,4-dihydro-5′-[(1R)-1-hydroxyethyl] [2,2′-bifuran]-5(2H)-one	−	Cytotoxic	−
5	3,4-dihydro-5′-[(1R)-1-hydroxymethylethyl] [2,2′-bifuran]-5(2H)-one	−	Cytotoxic	−
6	Oblongolides D	−	Cytotoxic	−
7	Oblongolides H	−	Cytotoxic	−
8	Oblongolides P	−	Cytotoxic	−
9	Oblongolides V	−	Cytotoxic	−
10	Emodin	D. lithocarpus	Cytotoxic, Antibacterial	[15]
11	Arbutin	−	Cytotoxic	−
12	Cytoskyrin C	Diaporthe sp.	Cytotoxic, Activate the NF-KB pathway	[24]
13	(+)-epicytoskyrin	−	Cytotoxic, Activate the NF-KB pathway	−
14	Vochysiamide B	D. vochysiae LGMF1583	Cytotoxic, Antibacterial	[8]
15	2,5-dihydroxybenzyl alcohol	−	Cytotoxic	−
16	Mycoepoxydiene	Diaporthe sp. SNB-GSS10	Cytotoxic	[6]
17	Eremofortin F	−	Cytotoxic	−
18	Lithocarins B	D. lithocarpus A740	Cytotoxic	[9]
19	Lithocarins C	−	Cytotoxic	−
20	Xylarolide	D. terebinthifolii GG3F6	Cytotoxic, Antibacterial	[12]
21	Xylarolide A	Diaporthe sp.	Cytotoxic	[25]
22	18-des-hydroxy cytochalasin H	D. phaseolorum-92C	Cytotoxic, Antioxidant	[26]
23	Diaporol R	Diaporthe sp.	Cytotoxic	[27]
24	Diaporone A	Diaporthe sp.	Cytotoxic, Antibacterial	[28]
25	Diaporthichalasin D	Diaporthe sp. SC-J0138	Cytotoxic	[29]
26	Diaporthichalasin E	−	Cytotoxic	−
27	Diaporthichalasin F	−	Cytotoxic	−
28	Diaporthichalasin H	−	Cytotoxic	−
29	Diaporthichalasin A	−	Cytotoxic	−
30	Diaporthichalasin B	−	Cytotoxic	−
31	Diaporthichalasin C	−	Cytotoxic	−
32	Phomopsichalasin G	−	Cytotoxic	−
33	21-O-deacetyl-L-696,474	−	Cytotoxic	−
34	Phomopthane A	D. unshiuensis YSP3	Cytotoxic	[30]
35	(10S)-diaporthin	D. terebinthifolii LGMF907	Antibacterial	[31]
36	Orthosporin	−	Antibacterial	−
37	Kongiidiazadione	D. kongii	Antibacterial	[32]
38	Coumarin	D. lithocarpus	Antibacterial	[15]
39	1,2,8-trihydroxyanthraquinone	−	Antibacterial	−
40	Phomosines A	Diaporthe sp. F2934	Antibacterial	[11]
41	Phomosines C	−	Antibacterial	−
42	19-nor-lanosta-5(10),6,8,24-tetraene- 1α,3β,12β,22S-tetraol	Diaporthe sp. LG23	Antibacterial	[14]
43	3b,5a,9a-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one	−	Antibacterial	−
44	Chaxine C	−	Antibacterial	−
45	Diapolic acid A	D. terebinthifolii GG3F6	Antibacterial	[12]
46	Diapolic acid B	−	Antibacterial	−
47	Phomolide G	−	Antibacterial	−
48	21-acetoxycytochalasins J3	Diaporthe sp. GDG-118	Antibacterial	[33]
49	Flavomannin-6,60-di-O-methyl ether	D. melonis	Antibacterial	[34]
50	Tyrosol	D. helianthi, D. eres	Antibacterial, Phytotoxic	[35,39,42]
51	3-methoxy-5-methylnaphthalene-1, 7-diol	Diaporthe sp.	Antibacterial	[36]
52	Alternariol methyl ether-12-O-α-D-arabinoside	D. unshiuensis YSP3	Antibacterial	[30]
53	Phomopsolide A	D. maritima	Antifungal	[5]
54	Phomopsolide B	−	Antifungal	−
55	Phomopsolide C	−	Antifungal	−
56	(S,E)-6-(4-hydroxy-3-oxopent-1-en-1-yl)-2H-pyran-2-one	−	Antifungal	−
57	7-hydroxy-6-metoxycoumarin	D. lithocarpus	Antifungal	[15]
58	(+)-2,20-epicytoskyrin A	Diaporthe sp. GNBP-10	Antifungal	[37]
59	7-acetoxycytochalasin H	Diaporthe sp. GDG-118	Antifungal	[32]
60	Cytochalasin H	−	Antifungal	−
61	Cytochalasin E	−	Antifungal	−
62	3-hydroxy-5-methoxyhex-5-ene-2,4-dione	Diaporthe sp. ED2	Antifungal	[16]
6	Eucalyptacid A	D. eucalyptorum KY-9	Antifungal	[13]
64	Cytosporone C	−	Antifungal	−
65	1-(4-hydroxyphenyl) ethane-1,2-diol	−	Antifungal	−
66	(2-hydroxy-2-phenylethyl) acetamide	−	Antifungal	−
67	Mucorisocoumarin A	D. pseudomangiferaea	Antifibrosis	[38]
68	Pestalotiopsone B	−	Antifibrosis	−
69	Acetoxydothiorelone B	−	Antifibrosis	−
70	Dothiorelone B	−	Antifibrosis	−
71	Dothiorelone L	−	Antifibrosis	−
72	Dothiorelone G	−	Antifibrosis	−
73	Cytosporone D	−	Antifibrosis, Antioxidant, Antidiabetic	−
74	3,4-dihydro-8-hydroxy-3,5- dimethylisocoumarin	D. eres	Phytotoxic	[39]
75	Diportharine A	Diaporthe sp.	Antioxidant	[25]
76	Diaportheone A	Diaporthe sp. P133	Antitubercular	[40]
77	Diaportheone B	−	Antitubercular	−
78	Phyllostine acetate	D. miriciae	Antifeedant	[41]
79	Phyllostine	−	Antifeedant	−
80	P-cresol	D. eres	Phytotoxic	[42]
81	4-hydroxybenzoic acid	−	Phytotoxic	−
82	4-hydroxybenzaldehyde	−	Phytotoxic	−
83	Nectriapyrone	−	Phytotoxic	−
84	Diaporthol A	Diaporthe sp. ECN-137	Antimigratory	[43]
85	Diaporthol B	−	Antimigratory	−
86	Gulypyrone A	D. gulyae	Phytotoxic	[44]
87	Phomentrioloxin B	−	Phytotoxic	−
88	Phomolide C	Diaporthe sp.	Antiproliferation effect	[45]
89	Diaporthsin E	Diaporthe sp. JC-J7	Antihyperlipidemic	[46]
90	2-hydroxy-alternariol	Diaporthe sp. CB10100	Reduced NO production	[47]
91	Alternariol	−	Reduced NO production	−
92	Phomentrioloxin	Phomopsis sp.	Phytotoxic	[48]
93	Diaporthindoic acid	D. lithocarpus	Inactive	[15]
94	2-phenylethanol	−	Inactive	−
95	Vochysiamides A	D. vochysiae LGMF1583	Inactive	[8]
96	Altiloxin A	D. pseudomangiferae	Inactive	[6]
97	Tenllone I	D. lithocarpus A740	Inactive	[9]
98	Lithocarin D	−	Inactive	−
99	Phomopene	−	Inactive	−
100	Xylarolide B	Diaporthe sp.	Inactive	[25]
101	Diaporol J	Diaporthe sp.	Inactive	[27]
102	Diaporol K	−	Inactive	−
103	Diaporol L	−	Inactive	−
104	Diaporol M	−	Inactive	−
105	Diaporol N	−	Inactive	−
106	Diaporol O	−	Inactive	−
107	Diaporol P	−	Inactive	−
108	Diaporol Q	−	Inactive	−
109	Diaporol S	−	Inactive	−
110	Alternariol 4,10-dimethyl ether	Diaporthe sp.	Inactive	[28]
111	Alternariol 4-methyl ether	−	Inactive	−
112	4H-1-benzopyra-4-one-2,3-dihydro-5-hydroxy-2,8-dimetyl	Diaporthe sp. F2934	Inactive	[11]
113	4H-1-benzopyran-4-one-2,3-dihydro-5-hydroxy-8-(hydroxy-lmethyl)-2-methyl	−	Inactive	−
114	Phomosine D	−	Inactive	−
115	3β,5α,9α,14α-tetrahydroxy-(22E,24R)-ergosta-7,22-dien 6-one	Diaporthe sp. LG23	Inactive	[14]
116	(22E,24R)-ergosta-7,9(11),22-triene-3β,5α,6α-triol	−	Inactive	−
117	Demethylincisterol A3	−	Inactive	−
118	Volemolide	−	Inactive	−
119	Diaporthemin A	D. melonis	Inactive	[34]
120	Diaporthemin B	−	Inactive	−
121	Eucalactam B	D. eucalyptorum KY-9	Inactive	[13]
122	Eugenitol	−	Inactive	−
123	4-hydroxyphenethyl alcohol	−	Inactive	−
124	(9S, 17R, 19S, 6Z, 10E, 14E)-Diaporlactone A	D. pseudomangiferaea	Inactive	[38]
125	5-hydroxy-7-methoxy-4,6-dimethyl-2-phenylisoindoline-1,3-dione	−	Inactive	−
126	(13R)-Diaporphthalide	−	Inactive	−
127	(15S)-Acetoxydothiorelone A	−	Inactive	−
128	Dothiorelone K	−	Inactive	−
129	Dothiorelone M	−	Inactive	−
130	Dothiorelone N	−	Inactive	−
131	16-acetoxydothiorelone C	−	Inactive	−
132	Dothiorelone A	−	Inactive	−
133	Dothiorelone C	−	Inactive	−
134	Dothiorelone I	−	Inactive	−
135	9-O-acetyl derivative	D. gulyae	Inactive	[44]
136	9-O-S-MTPA ester	−	Inactive	−
137	9-O-R-MTPA ester	−	Inactive	−
138	Gulypyrone B	−	Inactive	−
139	Phomentrioloxin C	−	Inactive	−
140	4-methylbenzoic acid	−	Inactive	−
141	3-nitropropionic acid	−	Inactive	−
142	Succinic acid	−	Inactive	−
143	Nectryapyrone	−	Inactive	−
144	Diaporthsin A	Diaporthe sp. JC-J7	Inactive	[46]
145	Diaporthsin F	−	Inactive	−
146	Diaporthsin H	−	Inactive	−
147	Diaporthsin C	−	Inactive	−
148	Diaporthsin B	−	Inactive	−
149	Diaporthsin D	−	Inactive	−
150	Diaporthsin G	−	Inactive	−
151	Diaporthsin I	−	Inactive	−
152	Diaporthsin J	−	Inactive	−
153	Diaporthsin K	−	Inactive	−
154	α-Pyrone	Diaporthe sp. CB10100	Inactive	[47]
155	Dothideopyrone F	−	Inactive	−
156	Ellagic acid	−	Inactive	−
157	Dibenzo-α-pyrone	−	Inactive	−
158	Ellagic acid B	−	Inactive	−
159	Diaporpyrone A	−	Inactive	−
160	Diaporpyrone B	−	Inactive	−
161	Diaporpyrone C	−	Inactive	−
162	Diaporpyrone D	−	Inactive	−
163	Diaporthichalasin G	Diaporthe sp. SC-J0138	Inactive	[29]
164	Phomopthane B	D. unshiuensis YSP3	Inactive	[30]
165	Phomopyrone B	−	Inactive	[30]

Table 2

Secondary metabolites associated with marine origin.

No.	Compound	Producing Strain	Active/Inactive	Ref.
60	Cytochalasin H	Diaporthe amygdali SgKB4, Diaporthe sp. GZU-1021	Antibacterial, Anti-NO production	[49,55]
166	3-hydroxypropionic acid	D. phaseolorum	Antibacterial	[50]
167	Diaporthelactone	Diaporthe sp.	Antifungal, Cytotoxic	[51]
168	Isochromophilone G	D. perseae	Antibacterial, Anti-inflammatory	[52]
169	Isochromophilone A	−	Antibacterial, Anti-inflammatory	−
170	Isochromophilone B	−	Antibacterial, Anti-inflammatory	−
171	5-chloroisorotiorin	−	Antibacterial, Anti-inflammatory	−
172	epi-isochromophilone II	D. perseae, Diaporthe sp. SCSIO 41011	Antibacterial, Cytotoxic, Anti-inflammatory	[52,57]
173	Isochromophilone III	D. perseae	Antibacterial, Anti-inflammatory	[52]
174	Penicilazaphilone D	D. perseae	Antibacterial, Anti-inflammatory	[52]
175	Pestalotiopsones F	Diaporthe sp. SCSIO 41011	Anti-IAV	[53]
176	Pestalotiopsones B	−	Anti-IAV	−
177	3,8-dihydroxy-6-methyl-9-oxo-9Hxanthene- 1-carboxylate	−	Anti-IAV	−
178	Phomoxanthone A	D. phaseolorum FS431	Cytotoxic	[54]
179	Biatriosporin N	Diaporthe sp. GZU-1021	Anti-NO production	[55]
180	Penialidin A	−	Anti-NO production	−
181	(−)-phomopsichin B	Diaporthe sp. GZU-1021, D. phaseolorum SKS019	Anti-NO production, Antiosteoclastogenesis	[55,56]
182	21-O-deacetyl-L-696,474	Diaporthe sp. GZU-1021	Anti-NO production	[55]
183	(−)-phomopsichin A	D. phaseolorum SKS019	Antiosteoclastogenesis	[56]
184	(+)-phomopsichin A	−	Antiosteoclastogenesis	−
185	(+)-phomopsichin B	−	Antiosteoclastogenesis	−
186	Diaporchromanone C	−	Antiosteoclastogenesis	−
187	Diaporchromanone D	−	Antiosteoclastogenesis	−
188	Isochromophilone D	Diaporthe sp. SCSIO 41011	Cytotoxic	[57]
189	Diaporisoindole A	Diaporthe sp. SYSU-HQ3	Cytotoxic	[58]
190	Tenellone C	−	Cytotoxic	−
191	Diaporindene A	Diaporthe sp. SYSU-HQ3	Anti-inflammatory	[59]
192	Diaporindene B	−	Anti-inflammatory	−
193	Diaporindene C	−	Anti-inflammatory	−
194	Diaporindene D	−	Anti-inflammatory	−
195	Isoprenylisobenzofuran A	−	Anti-inflammatory	−
196	Diaporisoindole D	−	Anti-inflammatory	−
197	Diaporisoindole E	−	Anti-inflammatory	−
198	Tenellone D	−	Anti-inflammatory	−
199	Cordysinin A	D. arecae	Antiangiogenic	[60]
200	5-deoxybostrycoidin	D. phaseolorum SKS019	Cytotoxic	[61]
201	Fusaristatin A	−	Cytotoxic	−
202	Phomopsin F	D. toxica	Cytotoxic	[62]
203	Longidiacid A	Diaporthe longicolla FS429	Enzymatic activity	[63]
204	Longichalasin B	−	Enzymatic activity	−
205	Diaporpenoid A	Diaporthe sp. QYM12	Anti-inflammatory	[64]
206	Diaporpyrone A	−	Anti-inflammatory	−
207	Secocurvularin	Diaporthe sp. SCSIO 41011	Inactive	[53]
208	Pestalotiopsone H	−	Inactive	−
209	Pestalotiopsone A	−	Inactive	−
210	(±)-microsphaerophthalide H	−	Inactive	−
211	Microsphaerophthalide I	−	Inactive	−
212	5-hydroxy-7-methoxy-4,6-dimethylphthalide	−	Inactive	−
213	Dihydrovermistatin	−	Inactive	−
214	Methyl convolvulopyrone	−	Inactive	−
215	Sclerotinin A (a)	−	Inactive	−
216	Sclerotinin A (b)	−	Inactive	−
217	3,5-dimethyl-8-hydroxy-3,4-dihydroisocoumarin	−	Inactive	−
218	3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin	−	Inactive	−
219	methyl 8-hydroxy-6-methyl-9-oxo-9Hxanthene-1-carboxylate	−	Inactive	−
220	Pinselin	−	Inactive	−
221	7-hydroxy-2,5-dimethylchromone	−	Inactive	−
222	Phaseolorin G	D. phaseolorum FS431	Inactive	[54]
223	Phaseolorin H	−	Inactive	−
224	Phaseolorin I	−	Inactive	−
225	Dicerandrol B	−	Inactive	−
226	2,20,60-trihydroxy-4-methyl-6-methoxy-acyl-diphenylmethanone	−	Inactive	−
227	Diaporchromanone A	D. phaseolorum SKS019	Inactive	[56]
228	Diaporchromanone B	−	Inactive	−
229	(±)-diaporchromone A	−	Inactive	−
230	Isochromophilone C	Diaporthe sp. SCSIO 41011	Inactive	[57]
231	Isochromophilone E	−	Inactive	−
232	Isochromophilone F	−	Inactive	−
233	epi-isochromophilone III	−	Inactive	−
234	6-((1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde	−	Inactive	−
235	(2E,4E)-1-(2,6-dihydroxy-3,5-dimethylphenyl)hexa-2,4-dien-1-one)	−	Inactive	−
236	Diaporisoindole B	Diaporthe sp. SYSUHQ3	Inactive	[58]
237	Diaporisoindole C	−	Inactive	−
238	Arecine	D. arecae	Inactive	[60]
239	Cyclo(L-Thr-L-Pro)	−	Inactive	−
240	Cyclo(6-hydroxy-Pro-L-Leu)	−	Inactive	−
241	Cyclo(L-Val-L- Pro)	−	Inactive	−
242	Bacillusamide B	−	Inactive	−
243	Cyclo(L-Leu-L-Pro)	−	Inactive	−
244	Cyclo(L-Val-L-Ala)	−	Inactive	−
245	Cyclo(L-Leu-L-Ala)	−	Inactive	−
246	Cyclo(L-Ile-L-Ala)	−	Inactive	−
247	Cyclo(Gly-L-Val)	−	Inactive	−
248	Cyclo(Gly-L-Leu)	−	Inactive	−
249	Cyclo(Gly-L-Ile)	−	Inactive	−
250	Cyclo(L-Ile-D-Pro)	−	Inactive	−
251	Staphyloamide A	−	Inactive	−
252	Cyclo(L-Ala-L-Pro)	−	Inactive	−
253	Cyclo(L-Ser-L-Pro)	−	Inactive	−
254	Cyclo(L-Trp-L-Pro)	−	Inactive	−
255	Cyclo(L-Tyr-L-Pro)	−	Inactive	−
256	Cyclo(L-Phe-L-Ala)	−	Inactive	−
257	Cyclo(L-Ser-L-Phe)	−	Inactive	−
258	Cyclo(D-Tyr-L-Leu)	−	Inactive	−
259	Cyclo(Gly-L-Trp)	−	Inactive	−
260	Cyclo(L-Trp-L-Ser)	−	Inactive	−
261	Diaporphasine A	D. phaseolorum	Inactive	[61]
262	Diaporphasine B	−	Inactive	−
263	Diaporphasine C	−	Inactive	−
264	Diaporphasine D	−	Inactive	−
265	Meyeroguilline C	−	Inactive	−
266	Meyeroguilline D	−	Inactive	−
267	Meyeroguilline A	−	Inactive	−
268	Longidiacid B	D. longicolla FS429	Inactive	[63]
269	Longichromone A	−	Inactive	−
270	Longiphthalidin A	−	Inactive	−
271	Acetophthalidin	−	Inactive	−
272	Longichalasin A	−	Inactive	−
273	Cytochalasin J3	−	Inactive	−
274	Diaporpenoid B	Diaporthe sp. QYM12	Inactive	[64]
275	Diaporpenoid C	−	Inactive	−

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