A Recent Overview of 1,2,3-Triazole-Containing Hybrids as Novel Antifungal Agents: Focusing on Synthesis, Mechanism of Action, and Structure-Activity Relationship (SAR)

Abstract

A pharmacophore system has been found as 1,2,3-triazole, a five-membered heterocycle ring with nitrogen heteroatoms. These heterocyclic compounds can be produced using azide-alkyne cycloaddition processes catalyzed by ruthenium or copper. The bioactive compounds demonstrated antitubercular, antibacterial, anti-inflammatory, anticancer, antioxidant, antiviral, and antidiabetic properties. This heterocycle molecule, in particular, with one or more 1,2,3-triazole cores has been found to have the most powerful antifungal effects. The goal of this review is to highlight recent developments in the synthesis and structure-activity relationship (SAR) investigation of this prospective fungicidal chemical. Also there have been explained drugs and mechanism of action of a triazole compound with antifungal activity. This review will be useful in a variety of fields, including medicinal chemistry, organic chemistry, mycology, and pharmacology.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

One of the most important fields of medicinal chemistry is the study of heterocyclic bioactive molecule containing nitrogen atoms [1, 2]. Triazole have been found as a potential heterocyclic component in a wide range of drug scaffolds. It has a five-membered nitrogen heterocycle core with three nitrogen atoms and two carbon atoms. The core has a substantial impact on biological activity [3]. The influences of the nitrogen heteroatom on the reactivity of the lead compound target medication pharmacokinetics and metabolism are affected by interactions between the lead chemical and several target inhibitors [4].

A fungus is one of the most diverse organisms in the world. Since eukaryotes share many potential drug-receptor targets with humans [5], the synthesis of the new fungicidal compounds with high selectivity is essential for fungal receptors and low affinity for human receptors [6, 7]. There are approximately recognized two million fungi types and 600 fungi species as human fungal pathogens with only 3-4% of these species leading to fungal infection [8]. Unfortunately, this kind of invasive fungal infections resulted in a high mortality rate [9]. Fungal infections have recently risen and are responsible for 1-2 million fatalities annually [10]. Most of the deaths (∼90%) are assigned to the Aspergillus and Candida species [11]. Invasive candidiasis species including Candida tropicalis, Candida glabrata, Candida parapsilosis, Candida krusei, and Candida albicans enhanced rate of mortality (75%). Furthermore, the Aspergillosis family containing fumigatus, niger, flavus, terreus, and parasiticus caused mortality rate of 50–90% [12]. Azole derivatives achieved antifungal activity by linking ergosterol in the active site of the cell membrane [13]. Researchers confirm that azoles with inhibiting the lanosterol 14α-demethylase enzyme inhibit the synthesis of ergosterol [14]. Certain 1,2,3-triazole derivatives have been generated and evaluated for antifungal activity in the last few years, with some potential activity against different fungi. This review is focused on the latest papers (2015–2021) on the synthesis of new series of 1,2,3-triazole antifungal agents and the evaluation of structure-activity relationship (SAR) to provide insight into the logical synthesis of more effective 1,2,3-triazole antifungal candidates. The process of selecting publications for this review is reported in the diagram below (Figure 1).

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Sharpless proposed the term “click chemistry” in 2001, which is explained as “chemistry tailored to produce a substance by linking small molecules together very quickly and simply” [17, 18]. Separately, Tornøe et al. [19] and Rostovtsev et al. [20] used Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as one of the most reliable click reactions to generate 1,2,3-triazole derivatives. Sharpless demonstrated reactions with high yields, moderate reaction conditions, the generation of stereospecific products without the need of chromatography, and ease of use.

The copper-catalyzed reaction, in particular, leads to the synthesis of 1,4-disubstituted regioisomers; this suitable reaction can be accomplished in aqueous solutions, even at room temperature [21, 22]. However, researchers discovered that ruthenium-catalyzed reaction yields 1,5-disubstituted triazoles with opposite regioselectivity [23] (Scheme 2).

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This exothermic reaction occurs at high temperatures, as illustrated in Scheme 4, despite the fact that the rate of reaction is insignificant. Since the layers’ two potential HOMO-LUMO interactions are nearly dependent in terms of energy, this results in almost 1 : 1 mixes in both the 1,5-substituted and 1,4-substituted regioisomers [20].

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The mechanism of CuAAC is described in Scheme 6. Firstly, sodium ascorbate as a reducing agent can produce active Cu(I) from Cu(II) salts. Homocoupling products are not produced by adding a small amount of sodium ascorbate. In addition, DFT computations confirmed that the coordination of an alkyne to Cu(I) is somewhat endothermic in MeCN but exothermic in water. The rate of reaction then increased in water. DFT analysis showed that acetylene coordination to Cu does not catalyze a 1,3-dipolar cycloaddition. As shown in Scheme 6, a π-bound copper coordinates with the azide. The intermediate copper metallacycle is then prepared. The second copper atom acts as a stabilizing donor ligand. Finally, the catalytic cycle is closed with the generation of a triazolyl-copper derivative. As a result, 1,2,3-triazole derivatives are synthesized by Proteolysis [27].

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The mechanism of the ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) is shown in Scheme 8; therefore, RuAAC appears from an oxidative coupling of the alkyne and the azide, yielding a six-membered ruthenacycle. The initial carbon-nitrogen bond is formed between the terminal nitrogen of alkyne and azide in the next step. The product 1,2,3-triazole is then formed by reductive elimination [28].

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(2) Synthesis of Radezolid. Oxazolidinones are an antimicrobial agent with a wide range of activity toward important Gram-positive and nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), enterococci, and pneumococci [37]. N-{[(5S)-3-[3-Fluoro-4-(4-{[(1H-1,2,3-triazole-5-ylmethyl)amino]methyl}phenyl)phenyl]-2-oxo-1,3-oxazo-lidin-5-yl]methyl}acetamide (Radezolid) is a new antibacterial agent of biaryl oxazolidinone that is in clinical expansion; the first clinical experiments were performed on simple skin and skin structure infections (uSSSI) and the second on community-acquired pneumonia (CAP) [38–40].

The most significant stage in Radezolid synthesis is the cross-coupling reaction of the iodooxalidinone derivative 13 and boroorganic acid derivative 18 catalyzed by tetrakis-(triphenylphosphine)palladium(0) relying on Suzuki reaction mechanism. Compound 18 was acquired by combining 4-methoxybenzyl chloride with the triazole ring. Intermediate 13 was provided from R-glycidyl butyrate and an introduced starting material to be used in the reaction of a carbamate, N-carboxyloxy-3-fluoroaniline, an oxazolidinone ring, allowing only one, enantiomerically pure, desired oxazolidinone derivative to be produced in four simple steps. Gravestock and coworkers [41] proposed critical modifications to the synthesis of Radezolid that focused on the phase leading to compound 19. Other changes included raising the number of solvents and increasing the amount of a novel one, extending the reaction time and temperature, and using a contemporary approach including crystallization of the terminal product 21 (Schemes 11 and 12) [42].

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(3) Synthesis of Carboxyamidotriazole (CAI). Carboxyamidotriazole (CAI) was initially developed as a noncytotoxic anticancer drug. Numerous studies [43–46] show that carboxyamidotriazole (CAI) has moderate anticancer efficacy in vitro and in vivo. Despite this, many preclinical investigations have revealed its antiproliferative, antiangiogenic, and antimigratory properties [44, 45, 47, 48].

In the proposed synthesis scheme, compound 22 is reacted with 24 to produce compound 25 after the alcohol group is shielded as the tert-butyldimethylsilyl (TBDMS) ether step (23). To form 3,5-dichloro-4-(4-chlorobenzoyl)benzyl azide, benzophene is reacted with thionyl chloride 26 and then with sodium azide (27). The reaction of cyanoacetamide with this azide constructs L651582 (29). Compounds 29 and 30 were produced by the interaction of component 29 with orotic acid (Scheme 13) [49].

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(4) Synthesis of Cefatrizine. Cefatrizine is a wide-spectrum cephalosporin antibiotic [50] and one of the first 3-heterocyclic thiomethylcephalosporins produced in the laboratories [51]. Cephalosporin compounds are replaced at the 3-situation by a heterocyclic thiomethyl group and at the 7-position by free or substituted α-aminophenylacetamido. They are synthesized by combining a 3-acetoxymethyl ring to a mercaptoheterocycle. Antibacterial factors are found in products (Scheme 14) [51].

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(5) Synthesis of Tertbutyldimethylsilylspiroaminooxathioledioxide (TSAO). TSAO reported a completely novel class of HIV-1-particular factors in 1992 [52–56]. Human replication of immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), or RNA viruses, and other DNA are inhibited by TSAO nucleoside analogs. They are designed to interact with RT-virus encoding at a nonsubstrate binding position [57, 58].

The 5-N-alkyl carbamoyl substituted TSAO triazoles were synthesized in two phases, with the aim of obtaining the 5-substituted 1,2,3-triazole derivative 36 [59] by reacting the azide intermediate 34 [59] with 2-oxo-alkylidentriphenyl-phosphorane 35 [60] in refluxing xylene. Compound 37 was synthesized by aminolyzing these ester derivatives with the proper amine (Scheme 15) [61, 62].

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Azole antifungal drugs have shown a modern period in antifungal chemotherapy. Despite sharing a similar mechanism, they vary in pharmacokinetics, toxicity, and fungal spectrum (Table 1) [66]. Other key factors in the early steps of development may increase the options available in this significant group of compounds. The addition of broad-spectrum triazoles provides physicians with more effective and less toxic alternatives to Amphotericin B [67].

Table 1

Mechanism of action of 1,2,3-triazole-based marketed drugs.

Name	Type of triazole	Mechanism of action	Ref.
Cefatrizine	4-monosubstituted	Second-generation cephalosporin.Cefatrizine is utilized to treat many types of infections, including respiratory tract, skin, ear, and urinary tract infections.	[51][66]
Tazobactam	1-monosubstituted	Powerful irreversible β-lactamase (SHV-1 and TEM) inhibitory activity and very low antibacterial activity. Tazobactam is combined in the drug piperacillin/tazobactam, which is used in infections caused by Pseudomonas aeruginosa.	[34, 66]
Carboxyamidotriazole (CAI)	1,4,5-trisubstituted triazole	CAI has antiangiogenic, antimetastatic, and antitumor properties owing to its ability to indirectly participate in the Store-Operated Calcium Entry.	[66]
Radezolid	4-monosubstituted	Antibiotic, active against bacteria (Gram-negative and Gram-positive) that connect to the 50S ribosomal subunit. Radezolid has been used in the treatment of abscess and infectious skin diseases.	[40, 66]
TSAO	4- or 5-substituted 1,2,3-triazoles	TSAO nucleoside analogs inhibit human replication of immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), or RNA viruses and other DNA	[61]

2.4. Review of the Latest Papers in the Synthesis of Novel 1,2,3-Triazole as an Antifungal Agent and Evaluating Structure-Activity Relationship (SAR)

2.4.1. 1,2,3-Triazole-Coumarin, Chromene, and Pyrane Hybrids

A series of novel 1,2,3-triazole-tethered coumarin conjugates linked by N-phenyl acetamide were effectively generated in high yields. Investigation of antifungal effect was performed against Fusarium oxysporum, Candida albicans, Aspergillus niger, Cryptococcus neoformans, and Aspergillus flavus. As shown in Figure 3, Compounds 39a, 39b, 39c, 40a, and 40b showed a high antifungal activity compared with Miconazole [68].

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Dharavath et al. [69] reported a method for synthesizing several coumarin-based 1,2,3-triazole compounds using a copper(I)-catalyzed click reaction between different substituted aryl azides and the end alkynes. All of the synthesized compounds were investigated for in vitro fungistatic effect against three fungus strains, Aspergillus flavus, Fusarium oxysporum, and Aspergillus niger, and the results were compared with standard drug (Clotrimazole). Six compounds (41a–f) showed better efficacy in contrast with the three pathogenic fungi (Figure 4).

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A series of new 1,2,3-triazole derivatives of quinolinone, benzyl, and coumarin were synthesized and tested for antifungal activity (Figure 5). All of the azole derivatives were tested for antifungal activity against 8 different fungal strains, four of which were Candida species (yeast samples) and the other four were Aspergillus species (filamentous fungi). Almost all of the compounds demonstrated excellent antifungal efficacy. According to the findings of SAR investigations, electron withdrawing or donating groups do not seem to be a main factor in decreasing or increasing antifungal activity [70].

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A novel class of 1,2,3-triazole based on coumarin was synthesized and assessed for antifungal behavior against three fungi (Penicillium chrysogenum, Curvularia lunata, and Aspergillus niger). All of the compounds displayed modest to good activity toward P. chrysogenum, C. lunata, and A. niger strains (Figure 6) [71].

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Shaikh et al. [72] reported a class of new ethyl-7-((1-(benzyl)-1H-1,2,3-triazole-4-yl)methoxy)-2-oxo-2H-chromene-3-carboxylates as a possible fungicide. The fungicidal property assessed the impact of five human pathogenic fungal strains, like Candida albicans, Aspergillus flavus, Aspergillus niger, Fusarium oxysporum, and Cryptococcus neoformans. As shown in Figure 7, compounds 46a, 46b, 46c, and 46e had comparable activity against Candida albicans to Miconazole, while compound 46d was twofold more active than the standard drug, which is similar to Fluconazole against Candida albicans. When compared to Miconazole, compounds 46b (R₂ = Cl) and 46d (R₃ = F) displayed equivalent effectiveness against the fungal strain A. niger. The addition of a triazole ring to coumarin increased the antifungal activity of the synthesized compounds. The addition of a triazole ring to coumarin improved the antifungal activity of the synthesized compounds.

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Gondru et al. [73] developed a new series of triazole-thiazole hybrids using the multicomponent reaction approach. In vitro antimicrobial activity investigations were evaluated. The results showed that, among the synthesized compounds, 48a–d and 48e were active and exhibited activity that is equal to or more than that of the conventional medicine against several Candida strains. Although the compounds did not have a broad antifungal range, they were less active than the standard drug against some pathogenic strains (Figure 8).

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The 1H-1,2,3-triazole-tethered 4H-chromeneD-glucose conjugates were synthesized using click chemistry of tetra-O-acetyl-b-D-glucopyranosyl azide and propargyl ethers. As it is seen in Figure 9, the antifungal activities of 1H-1,2,3-triazoles against Aspergillus flavus (ATCC 204304), Aspergillus niger (ATCC439), Saccharomyces cerevisiae (SH 20), and Candida albicans (ATCC7754) were evaluated. Fluconazole and Miconazole were used as standard drugs. Surprisingly, nearly all tested diazoles were more active against fungi C. albicans, S. cerevisiae, and A. flavus. Nonetheless, the triazoles were more resistant to A. niger than standard drugs. In fungi A. niger, approximately all of the compounds were less active than common medicines, with the exception of triazole 49c, with an MIC value of 1.56 μM. Compound 49a was more active against C. albicans than Miconazole but less active than Fluconazole, and compounds 49f and 49g against S. cerevisiae were more active than Miconazole. In total, triazoles with big groups (methyl, methoxy, and isopropyl) in their phenyl ring were less active. Nevertheless, there are several unusual compounds (49b, 49c, and 49e) [74].

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Khare et al. [75] developed a green and impressive protocol for the synthesis of new 1,2,3-triazole-chromene conjugates using ultrasound-assisted and NaHCO₃-catalyzed reactions. Triazole-chromene compounds were evaluated for fungicidal activity against five different fungal strains: Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, Cryptococcus neoformans, and Candida albicans, and several of them (50a–f) showed stronger activity (MIC = 6.25–25 μg/mL) compared to the standard drug Miconazole. Compound 50d (with R = 2-OMe) was more active than Miconazole against C. albicans and displayed less antifungal activity against remaining fungal strains. Only compound 50f has displayed greater activity against A. flavus as compared to the other strains (Figure 10).

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Dofe et al. [76] prepared a sequence of 3-((1-benzyl-1H-1,2,3-triazole-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-ones (51) via click chemistry. As shown in Figure 11, all of the compounds were tested for in vitro fungicidal activity toward Candida albicans, Candida tropicalis, and Candida glabrata. Significantly, 1,2,3-triazole-based chromones are more sensitive to C. glabrata and C. tropicalis fungal strains. When compared to the reference drug Miconazole, compounds 51a and 51b displayed equivalent activity against C. albicans. Compounds 51a and 51b with an MIC of 12.5 μg/mL are very strong antifungal agents against C. glabrata and C. tropicalis, respectively.

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Kant et al. [77] described the synthesis of 1,2,3-triazole-connected chalcone and flavone hybrids. The recent synthesized compounds were screened for their antifungal behavior toward Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Dermatophyte, and Candida albicans and also molds Aspergillus fumigatus and Aspergillus niger. Figure 12 shows that compounds 52b, 53a, 53b, 54a, 55a, 55b, 55c, 56a, and 56b displayed good antifungal behaviors as compared to the corresponding reference medications. Compound 52a, including 2-chloro-4-fluoro-substituted benzene ring, displayed modest to good activity with MIC ranges of 25–100 μg/mL and 100 μg/mL compared to Fluconazole in the range of 0.5–4.0 μg/mL against all examined strains. Flavone compounds 55a and 55b containing 2-chloro-4-fluoro- and 3-chloro-4-fluoro-substituted benzene ring in order displayed good activity against four strains. Amalgamation of chloro and fluoro atoms in benzene ring has greater antifungal activity than monohalogen compounds in one-triazole-connected flavones. But the existence of 2-chloro or its composition with fluoro group in phenyl ring displayed stronger activity than other groups and their combinations in flavones included two triazole units.

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A new model has been proposed and synthesized, consisting of the development of double pharmacophores of pyrano-[2,3-d]-pyrimidine-attached 1,2,3-triazole derivatives in an exceptional molecular hybrid with antimicrobial activity (bacteria and fungi). The antifungal efficacy of the target compounds toward Aspergillus flavus and Candida albicans is outstanding. Ketoconazole (zone of inhibition 14.0–20.5 μg/mL) was applied as the standard medicine for antifungal activity (Figure 13). Meanwhile, three compounds (57a–c) exhibited significant fungicidal activity against all of the studied fungi when compared to ketoconazole owing to groups (nitro and fluoro) linked to the 1,2,3-triazole of the pyranopyrimidine ring [78].

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A class of dehydroacetic acid chalcone-1,2,3-triazole hybrids were synthesized as possible antibacterial agents. All of the compounds were screened in vitro toward two fungal strains (Candida albicans and Aspergillus niger) and four bacterial strains (Figure 14). Almost all of the compounds performed better than DHA, which is an antimicrobial agent. The antifungal activity of combination 58h (R₁ = OCH₃) against A. niger and C. albicans showed MIC values of 0.0068 and 0.0034 μM/mL, respectively. When compared to A. niger, compounds 58a–h were more potent than the standard drug, but in the case of C. albicans, compounds 58g and 58h revealed significant activity among all synthesized triazoles [79].

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A new class of N-Boc L-Leucine-connected 1,2,3-triazoles were synthesized and evaluated the fungicidal activity against A. niger and Candida albicans fungus strains using an MIC value of 0.0102 μmol/mL. In case of both fungal strains, compounds 60a and 60b had approximately comparable activity with Fluconazole. Compounds 60a and 60c found a remarkable activity as compared to Fluconazole in the case of C. albicans (Figure 16) [81].

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Kaushik et al. [82] reported a novel library of 1,2,3-triazoles bridged with amine-amide functionalities from N-substituted (prop-2-yn-1-yl)amines and sodium azide and 2-bromo-N-arylacetamides by copper(I)-catalyzed. Antifungal assessment of recent derivatives was carried out against Aspergillus niger and Candida albicans. All compounds of synthesized 1,2,3-triazoles showed modest to good antifungal activity against fungi strains. Compounds 61a–f displayed good activity against C. albicans, while in case of A. niger, compounds 61b, 61c, and 61g displayed significant activity (Figure 17).

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The use of [Et₃NH][OAc] as a mediator in the performance of ultrasonic irradiation via click chemistry resulted in a simple, very impressive, and greener method for the preparation of novel 1,4-disubstituted-1,2,3-triazoles with high yields. These compounds were assessed in vitro for antifungal activity against five different fungus species: Aspergillus niger, Aspergillus flavus, Fusarium oxysporum, Cryptococcus neoformans, and Candida albicans. Some compounds have the same or greater power compared to the reference drug (Miconazole) (Figure 18) [83].

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Aryloxy-linked dimeric 1,2,3-triazoles from azides and bis(prop-2-yn-1-yloxy)benzene were synthesized by Deshmukh et al. [84] using a Cu(I)-catalyzed click chemistry approach with good to excellent yields. All of the compounds were tested for antifungal activity against five different fungal strains: Cryptococcus neoformans, Fusarium oxysporum, Aspargillus flavus, Aspargillus niger, and Candida albicans, and Miconazole is utilized as standard medicine. Most of the compounds showed moderate-to-great antifungal activity (Figure 19).

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Yan et al. [85] synthesized 42 carboxamide derivatives, including a 1,2,3-triazole ring, and demonstrated antifungal activity against nine phytopathogens at 50 μg/mL boscalid as the positive control. The target compounds in sequence A displayed more extraordinary inhibitory activities against G. graminsis, S. sclerotiorum, B. cinerea, and R. cerealis compared to other fungus strains. In sequence B, compounds showed fewer antifungal activities than series A. Compound 65A3-1 revealed remarkable antifungal activity against Sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia cerealis, and Gaeumannomyces graminsis, and it was chosen as the best compound for further investigation. When R of the benzene was monosubstituted, the inhibitory rate of 65A1-1 (p-Cl) was preferred over 65A1-2 (p-F) and 65A1-3 (p-OCH₃), while R of the benzene was disubstituted; the activity of 65A1-4 (3,4-di-Cl) was superior to those of 65A1-5 (3-Cl-4-F) and 65A1-6 (4-Cl-3-OCH₃) (Figure 20).

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Brahmi et al. [86] explored a novel sequence of semicarbazone-triazole hybrid derivatives with condensation among the commercial semicarbazide hydrochloride and heterocyclic aldehydes. The in vitro antifungal activities were examined against two fungus strains (Fusarium oxysporum and Fusarium phyllophilum) and showed the greatest inhibitory antifungal activity that was created for compound 66c against F. oxysporum in comparison to the standard drug. The ortho-methoxy substitution in the aryl ring (66e) is more acceptable for activity than the para-methoxy substituent (66d) because of the structure’s fixation by intramolecular H-bonds. The following antifungal activity levels were observed: 66c > 66e > 66d against F. oxysporum. 66a and 66b had low-to-moderate activity (Figure 21).

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Kaushik and Luxmi [87] examined a collection of 25 amides linked to 1,4-disubstituted 1,2,3-triazoles. The antifungal activity of two fungus strains was also studied using a serial dilution approach. Fluconazole was employed as a conventional treatment, and compounds 67a and 67b showed moderate intense activity (Figure 22).

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Kaushik and Luxmi [88] synthesized 2-(4-(hydroxyalkyl)-1H-1,2,3-triazol-1-yl)-N-substituted propanamides using Cu(I) catalyzed reaction of 2-azido-N-substituted propanamide and terminal alkynes. Furthermore, the antifungal activity of these triazoles was examined in vitro against two fungal strains (A. niger and C. albicans), with Fluconazole serving as a reference drug. Compounds 68a–c revealed powerful fungicidal activity against C. albicans and displayed good activity against A. niger (Figure 23).

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Amide-ester-connected 1,4-disubstituted 1,2,3-triazoles were synthesized by employing Copper(I)-catalyzed 1,3-dipolar cycloaddition of 2-azido-N-substituted acetamides and benzoic acid prop-2-ynyl esters. All of the compounds were evaluated for antifungal activity against two different fungus strains, Aspergillus niger and Candida albicans. The antifungal activity results revealed that most of the synthesized compounds exhibited moderate-to-good antifungal efficacy against the named fungus strains. Compound 69e including R₂ = electron-donating group and R₁ = p-Br-C₆H₄- had good antifungal activity against A. niger. R₁ and R₂ containing an electron-donating group, like methyl on both the benzoate and amino phenyl moieties (69i), showed good fungicidal activity against C. albicans (Figure 24) [89].

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Wang et al. [90] synthesized and tested novel hydrazide derivatives of 1,2,3-triazole for fungicidal activity against S. sclerotiorum, F. graminearum, M. oryzae, and R. solani. The findings revealed that all of the target compounds have notable antifungal activity. Compound 70b showed the most potent antiphytopathogenic activity, with EC₅₀ values of 0.18, 0.35, 0.37, and 2.25 μg/mL against the four fungi, respectively. Owing to the lower cost of fluorosubstituted aniline compared to chlorine-substituted aniline, 70b was chosen to experiment antifungal property in vivo despite the equal antifungal activity produced by other compounds. The EC50 values displayed that an electron-withdrawing group outperformed an electron-donating group for R₂ (Figure 25).

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Saidugari et al. [91] synthesized new 1,2,3-triazole-hydrazone derivatives with a 3,4-dimethoxy pyridine ring core. Different benzohydrazides and 2-(chloromethyl)-3,4-dimethoxypyridine 1,4-ethynylbenzaldehyde were produced using these compounds. They were tested for fungal stains such as Aspergillus niger and Candida albicans (Figure 26).

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A series of 5-nitrofuran-triazoles were synthesized with appropriate structural corrections of the formerly reported counterparts, and they were evaluated to examine 14 various fungal strains and were shown to have great antifungal activities. In comparison to one or more fungal strains examined, all compounds were comparable with Miconazole and showed good effectiveness against other equivalents. Compound 74a displayed twofold better antifungal activity (MIC = 3.9 μg/mL) compared to Miconazole (MIC = 7.8 μg/mL) against C. parapsilosis and C. albicans (Figure 27) [92].

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Li et al. [94] used click chemistry to design and synthesize reclaimed chitosan containing a 1,2,3-triazole scaffold with a different alcohol chain. To improve the antifungal activity of chitosan derivatives, molecules of varied lengths were used as functional dendrons. All of the derivatives showed great activity against the examed fungi (P. asparagi and C. lagenarium). The inhibitory indices of six chitosan derivatives 77 were greater than those of unmodified chitosan and quaternary ammonium chitosan 76 at the identical concentration. The results revealed that the triazolyl group linked to the synthesized chitosan derivatives contributed significantly to antifungal action, hence increasing their antifungal activity (Figure 29).

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Tan et al. [95] synthesized the 1,2,3-triazolium-functionalized starch derivative, and the efficacy of quaternization of the 1,2,3-triazole section with benzyl bromide on the antifungal screen of the starch derivative was evaluated by looking at the percentage inhibition of mycelial growth. These derivations displayed notable reclaimed antifungal behavior than starch derivative bearing 1,2,3-triazole and starch. Electrostatic and hydrophobic interactions may have a greater antifungal activity tangency than hydrogen bond interactions and higher inhibitory indices of 1,2,3-triazolium-functionalized starch derivatives compared with starch derivative containing 1,2,3-triazole (Figure 30).

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A novel group of inulin derivatives with 1,2,3-triazolium-charged parts by associating “click reaction” with impressive 1,2,3-triazole quaternization were synthesized. As shown in Figure 31, the antifungal tests revealed that compounds containing triazolium 80 inhibited the growth of tested phytopathogens more effectively than inulin derivatives, including triazoles 79. However, 1,2,3-triazolium exhibited a higher cationic charge, which was affected more by the interactions with anionic fragments in the fungal cell wall [96].

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Tan et al. [97] suggested a direct synthetic approach to novel starch derivatives with 1,2,3-triazolium- and pyridinium-charged units by linking CuAAC with impressive alkylation of pyridine and 1,2,3-triazole. Fungicidal activity against three plant-threatening fungi (Watermelon fusarium, Phomopsis asparagi, and Colletotrichum lagenarium) was estimated in vitro by hypha measurement. The antifungal activity of synthesized starch derivatives having 1,2,3-triazolium and pyridinium was higher than that of starch derivatives with 1,2,3-triazole and pyridine, implying that the alkylation of 1,2,3-triazole and pyridine was remarkable for raised antifungal activity (Figure 32).

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Based on the pioneer starch compounds N-alkylated with 1,2,3-triazole and iodomethane, four novel 1,2,3-triazolium-functionalized starch derivatives were synthesized (CuAAC). The antifungal activities of compounds against Fusarium oxysporum, Watermelon fusarium, and Colletotrichum lagenarium were tested in vitro by hypha measurement. C. lagenarium is the most sensitive pathogenic fungus yeast to the examined compounds. The inhibitory indices of all cases increase with increasing concentration ($P<0.05$) with 1.0 mg/mL exhibiting the greatest antifungal activity. Following a one-step alkylation with iodomethane, 1,2,3-triazolium-functionalized starch derivatives exhibit massively increased antifungal property with inhibitory indices of up to 60% at 1.0 mg/mL ($P<0.05$), compared with 1,2,3-triazole-functionalized starch derivatives with inhibitory indices of less than 10% ($P<0.05$). In general, the length of the alkyl groups was an effective determinant of 1,2,3-triazolium-functionalized starch derivative antifungal activity (Figure 33) [98].

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Li et al. [99] investigated three new chitosan derivatives, including 1,2,3-triazole with or without halogen. Their antifungal activity toward three kinds of phytopathogens was evaluated via hyphal mensuration in vitro. The inhibitory effects and water solubility of the synthesized chitosan derivatives were significantly superior to chitosan. CTCTS and BTCTS, which include halogens at the polymer’s edge, inhibited the development of the examined phytopathogens more impressively, with inhibitory indices ranging from 81 to 93% at 1.0 mg/mL (Figure 34).

[figure omitted; refer to PDF]

Nalawade et al. [101] demonstrated the formation of a series of 1-substituted benzyl-4-[1-phenyl-3-(4-methyl-2-aryl-1,3-thiazol-5-yl)-1H-pyrazol-4-yl]-1H-1,2,3-triazole. Almost most of the compounds showed good-to-high antifungal activity toward R. glutinis and A. niger. The antifungal activity suggests that these compounds can be preferred for improved optimization and spread, since they have the potential for behaving against fungal infections (Figure 36).

[figure omitted; refer to PDF]

Khare et al. [102] synthesized new 1,2,3-triazolyl pyrano [2,3-c]pyrazole derivatives in high yield using NaHCO₃ as a catalyst under ultrasonic irradiation. The observations showed that the antifungal activity was different from the substituent present on an aromatic unit of 1,2,3-triazolyl pyrano[2,3-c]pyrazole. Compound 87e revealed high antifungal activity, and it was more potent than Miconazole against C. albicans with MIC = 12.5 μg/mL; moreover, only this compound displayed equivalent activity against A. niger with MIC = 25 μg/mL (Figure 37).

[figure omitted; refer to PDF]

Bhat et al. [103] explained the synthesis of a new sequence of 1,2,3-triazolyl pyrazole derivatives, as well as antifungal investigations on the synthesized compounds against A. flavus, C. keratinophilum, and C. albicans. When compared to other fungal species, C. albicans was the most vulnerable. A. flavus and C. keratinophilum responded differently to each organic compound. Compounds 88a and 88b exhibited significant activity compared to the reference drug Fluconazole. The SAR also revealed the existence of multi-electron-withdrawing, liphophilic, and electronegative groups on phenyl rings, such as fluorine, chlorine, nitro, and trifluoromethyl, and electron-donating groups like quinyl and phthalazinyl, which may be more useful than the less substituted or unsubstituted groups on phenyl rings (Figure 38).

[figure omitted; refer to PDF]

Sindhu et al. [104] reported a new molecule sequence of pyridinone, 1,2,3-triazoles, and pyrazole. Two yeast strains, Saccharomyces cerevisiae and Candida albicans, were studied in vitro for fungicidal activity. As it is shown in Figure 39, all compounds had excellent antifungal activity, with MICs ranging from 64 to 256 μg/mL for C. albicans and from 64 to 256 μg/mL for S. cerevisiae. Compounds 89b and 89a displayed MIC values of 64 μg/mL against S. cerevisiae, which were lower than the reference Amphotericin B (APT-B).

[figure omitted; refer to PDF]

Dubovis et al. [105] designed and developed a novel and fundamental method for synthesizing 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles. As shown in Figure 40, antifungal screening of these compounds on a variety of phytopathogenic fungus has been explored. A significant alteration of the triazole ring of the halogen-substituted aromatic remainders displayed an enhancement of fungicidal activity in the final compounds. Compound 90a was substantially more active than its nonsubstituted or alkyl-substituted counterparts.

[figure omitted; refer to PDF]

Seven miconazole analogs, including 1,4,5-tri and 1,5-disubstituted triazole moieties, were developed and synthesized by azide-enolate 1,3-dipolar cycloaddition. The antifungal properties of these compounds were screened in vitro for three different Candida spp. as yeast samples and four penicillate fungi: Rhizopus oryzae, Mucor hiemalis, Trichosporon cutaneum, and Aspergillus fumigatus. Compound 91b was shown to be better than or equivalent to Itraconazole in its antifungal activity against the filamentous fungi R. oryzae, M. hiemalis, and T. cutaneum. When compared to the reference drug (MIC = 0.25 g/mL), compound 91c inhibited A. fumigatus growth only little (MIC 0.5 μg/mL) (Figure 41) [106].

[figure omitted; refer to PDF]

Rezki [107] described the synthesis and antimicrobial evaluation of new polyheterocyclic molecules based on the benzimidazole core of 1,2,3-triazole and 1,2,4-triazoles. As shown in Figure 42, triazoles 92a–c gave the most potent inhibition toward all of the tested fungal strains that were more powerful than the standard drug Fluconazole.

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Soltani Rad et al. [110] described a new class of fungicidal compounds known as 1,2,3-triazolyl β-hydroxy alkyl/carbazole hybrid molecules. The ’Click’ Huisgen cycloaddition reaction was carried out in the present of copper-doped silica cuprous sulfate. Compound 101a demonstrated strong antifungal activity against all fungal studies (Candida albicans (ATCC 10231), Aspergillus niger (ATCC 16404), Candida krusei (ATCC 6258), and Trichophyton rubrum (PTCC5143)) compared with Fluconazole and Clotrimazole as standard drugs. From the SAR viewpoint, since all of the studied compounds differ only in side chains, the differences in antifungal activity are ascribed to these changes (Figure 45).

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Huo et al. [111] reported two series of new aryl-1,2,3-triazole-β-carboline hybrids, and their antifungal activities were appraised in vitro against phytopathogenic species containing Fusarium oxysporum, R. solani, Botrytis cinerea Pers., sunflower sclerotinia rot, and rape sclerotinia rot using a 50 μg/mL mycelia growth inhibition test. In vitro, none of the target compounds displayed antifungal activity, with an inhibition rate of less than 20% against F. oxysporum (Figure 46).

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5-Fluoroindoline-2,3-dione-1-aryl-1H-triazole-4-yl methyl hybrid molecules were synthesized in aqueous conditions using a well-known CuAAC reaction applying Cell-CuI-NPs as a novel heterogeneous catalyst [112]. All synthesized compounds were analyzed against two fungal pathogens of Candida Albicans and Aspergillus niger and then Fluconazole (MIC = 0.0051–0.0102 μmol/mL) drug was applied. All synthesized compounds showed moderate-to-high antifungal activity (Figure 47).

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Sakly et al. [113] investigated a wide range of novel functionalized spirooxindole-pyrrolidine and spirooxindole-pyrrolizidine-connected 1,2,3-triazole conjugates. The compounds were examined in vitro for antifungal and antibacterial activity using the agar dilution procedure and showed appropriate activity. Compounds 106a and 107a were similarly potent against C. albicans as griseofulvin (Figure 48).

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Aouad [114] reported the discovery of new isatin-1,2,3-triazoles attached by morpholines, piperazines, or piperidines through a methylene or acetyl linkage and tested for antifungal activity against a panel of pathogenic fungal strains. Antimicrobial activity ensured the association of the action on the nature of the cyclic secondary amine added to the 1,2,3-triazole ring. The isatin-1,2,3-triazole hybrids including a piperazine unit were found to be the most active of the examined compounds (108a–c). Compounds with a piperazine moiety (109a–c) displayed the biggest antifungal inhibition activity (Figure 49).

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Shaikh et al. [115] described novel triazole-based isatin derivatives that were evaluated for biological activity using click chemistry. The 1,2,3-triazole-based isatin compounds showed good-to-moderate activity against all five human pathogenic fungal strains tested. The activity of 110b and 110c with chloro-group at meta and ortho situations in the phenyl ring displayed strong activity as compared with the standard drug against Fusarium oxysporum. Compound 110a with nitro-group at para position in the phenyl ring displayed equal activity against the fungicidal strain Candida albicans as compared with the reference medicine Miconazole (Figure 50).

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Shaikh et al. [117] investigated the biological activity of tetrazoloquinoline derivatives based on 1,4-disubstituted 1,2,3-triazole (Figure 52). All of the synthesized 1,4-disubstituted 1,2,3-triazole-based tetrazoloquinoline derivatives displayed good-to-moderate activity toward C. albicans, P. chrysogenum, C. lunata, A. niger, A. flavus, and C. neoformans strains. Compounds 113a–c revealed four times the activity against C. albicans strain compared to the standard medicine Miconazole and Amphotericin B and twice the activity compared to Fluconazole.

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Irfan et al. [118] reported the synthesis of 1,2,3-triazole derivatives that were evaluated on three various fungal strains, C. glabrata ATCC 90030, Candida tropicalis ATCC 750, and Candida albicans ATCC 90028, and the findings were compared with the reference drug (Fluconazole). The results of anticandidal activity were obtained from three various Candida strains. They showed that compound 114a outperformed Fluconazole with IC₅₀ values of 12.022 μg/mL against Candida glabrata, 0.044 μg/mL against Candida albicans, and 3.60 μg/mL against Candida tropicalis. Also, compounds 114a and 114b exhibited <5% hemolysis at their IC₅₀ values, demonstrating the nontoxic treatment of these inhibitors (Figure 53).

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The click reaction catalyzed by Cu(I) used a class of 1,2,3-triazole containing oxime products under both conventional and microwave irradiation conditions. The compounds were evaluated against two fungi (Aspergillus flavus and Aspergillus niger) using Nystatin as a standard medicine. Compounds 116a and 116b showed a better zone of inhibition, whereas compounds 116c–f exhibited a similar zone of inhibition comparable to the standard drug against the tested fungal strains (Figure 55) [120].

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A new class of 1,3-bis-(1,2,3-triazole-1-yl)-propan-2-ol derivatives were synthesized using various alkynes and 1-aryl-1,3-diazidopropan-2-ol derivatives, with the critical step including click reaction. When compared to Itraconazole and Fluconazole (MIC = 2.56 and 1.28 μg/mL, respectively), almost all of the synthesized compounds displayed great activity against Candida spp. strains in 0.04–0.5 μg/mL concentration ranges. The effect of cyclopropyl groups and fluorine atom in molecule 117a suggested a great selectivity in this compound to inhibit these type of Candida strains (Figure 56) [121].

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A new class of 1,2,4-triazole thione derivatives including substituted piperazine portions and 1,2,3-triazole were described by Wang et al. [122]. The results of the bioassay showed that several compounds have significant fungicidal activity toward a variety of plant fungi at 50 μg/mL. In most cases, trifluoromethyl-including triazole thione derivatives displayed desirable fungicidal activities that could be due to the great effects (like hydrophobicity and permeability) of the trifluoromethyl group reported on the parent structure (Figure 57).

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Pertino et al. [123] synthesized 24 novel triazole derivatives from the abietane diterpenes carnosic acid and carnosol through using click chemistry. The length of the linker and the substituent on the triazole portion differed among compounds. The compounds varied in the length of the linker and the substituent on the triazole section. Antifungal activity was determined against Cryptococcus neoformans (ATCC 32264) and Candida albicans (ATCC 10231). In terms of antifungal action, C. neoformans was the most susceptible fungus, with some compounds inhibiting more than 50% of its fungal growth at doses as low as concentrations ≤250 μg/mL. Compound 123b containing a p-Br-benzyl substituent on the triazole ring had the best activity (91% growth inhibition) at 250 μg/mL. In turn, six compounds prevented 50% C. albicans growth at concentrations further ess than 250 μg/mL. When comparing 122a and 122b with 122c and 122d (R₁: p-bromobenzyl), the existence of a Br in the aromatic ring did not shift the activity until the length of the linker was three CH₂ units; however, it decreased when the linker possessed two CH₂ units. Comparing the activities of 122a and 122b with those of 122e and 122f, introducing a nitro group in the aromatic ring (R₁: p-nitrobenzyl), the activity of the nitro compounds is lower (Figure 58).

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Thotla et al. [125] synthesized a new series of Benzo[b]thiophene triazoles with high yields from various azides with propargyl derivatives of benzothiophene, and most of them displayed significant antifungal activity against the fungi tested (Sclerotium rolfsii and Aspergillus niger) (Figure 60).

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Costa et al. [126] explained a new route for synthesizing a series of glycerol-derived 4-alkyl-substituted 1,2,3-triazoles using glycerol as the starting substance. Colletotrichum gloeosporioides, a causal factor of papaya anthracnose, were tested for fungicidal activity. All compounds inhibited mycelial development less effectively than the positive control Tebuconazole. Compounds 126a and 126b were the most active (ED50 values below 20 ppm), with 126b exhibiting the widest power (ED50 10.14 ppm) (Figure 61).

[figure omitted; refer to PDF]

Seventeen new benzoxazole derivatives, containing a 1,2,3-triazole scaffold, were generated in order to discover contemporary bioactive compounds with outstanding antifungal properties. The antifungal activities of the synthesized compounds were screened toward Fusarium verticillium (FV) and Botrytis cinerea (BC), with hymexazol serving as a positive control. The results of the tests showed that compounds 127a–d had good inhibitory effects on fungus. In these compounds, when the benzotriazole and benzoxazole moiety were without substituents at aromatic ring, they revealed the best antifungal activity against BC (127b). The compounds were more active against BC than against FV (Figure 62) [127].

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Straight and adaptive azide-enolate (3 + 2) cycloaddition was used to synthesize modern oxazolidin-2-one-connected-1,2,3-triazole derivatives. As it can be seen in Figure 63, the sequence of compounds was tested for fungicidal activity toward four penicillate fungi as well as six yeast species of Candida spp., and Itraconazole used as the reference antifungal drug. Compounds 128a–c showed higher activity against C. glabrata (MICs of 0.12, 0.25, and 0.12 μg/mL, respectively) than Itraconazole (MIC = 1 μg/ml). The activity of compound 128a (MIC = 2 μg/mL) against Trichosporon cutaneum was better than that of Itraconazole (MIC = 8 μg/mL), while compound 128c showed a great antimycotic activity in Mucor hiemalis (MIC = 2 μg/mL versus 4 μg/mL for Itraconazole) [128].

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González-Calderón et al. [129] reported the first synthesis of a new kind of compound, using 1′-homo-N-1,2,3-triazole-bicyclic carbonucleosides 129a and 129b that exhibited good activity against some of the yeast strains examined (Figure 64).

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The new benzofuran-triazole hybrids were generated using click reaction. The antifungal effect of goal compounds toward five strains of pathogenic fungi was assessed using the microdilution broth technique. The results showed that the lead compounds were active in a moderate-to-acceptable range. Some compounds only have a mild antifungal activity against Candida albicans and Rhodotorula rubra. With the exception of compounds 130a and 130b, most of the compounds displayed antifungal activity against Cryptococcus neoformans in concentrations ranging from 32 to 128 μg/mL. The primary SARs were supported by the excellent bioactivities of 130f and 130g among all the goal compounds (Figure 65) [130].

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A sequence of 4-((1-benzyl/phenyl-1H-1,2,3-triazole-4-yl)methoxy) benzaldehyde derivatives were generated in high yield. All compounds were examined for fungicidal activity against Aspergillus niger and Candida albicans in vitro. The majority of the compounds demonstrated good-to-outstanding antifungal activity. Compounds 132a and 132b were more potent against A. niger with MIC value of 0.0084 μM/mL compared to Fluconazole (MIC = 0.0102 μM/mL) (Figure 67) [132].

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Jiang et al. [133] explored a series of new paeonol derivatives linked to a 1,2,3-triazole moiety for obtaining modern bioactive compounds with remarkable fungicidal activity using Cu(OAc)₂·H₂O/sodium ascorbate as a catalyst and under mild conditions. The antifungal properties of all the target compounds were assessed in vitro against two plant pathogenic fungi: Rhizoctonia cerealis and Colletotrichum capsici. The outcomes of antifungal activities showed that several of the compounds had acceptable activity in vitro against the examined fungi at 20 μg/mL (Figure 68).

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He et al. [134] investigated the activity of 5-iodo-1,4-disubstituted-1,2,3-triazole compounds that were evaluated to study their Escherichia coli PDHc-E1 and fungicidal activity. Compound 135b had the most inhibitory activity (IC₅₀ = 4.21 ± 0.11 μM) and was shown to be an aggressive PDHc-E inhibitor. Fungicidal activity findings exhibited that compounds 135a–c had almost good activity against Botrytis cinerea and Rhizoctonia solani even at 12.5 μg/mL. The SAR resolution showed that the 4-situation in the benzene ring significantly influenced the antifungal effect and inhibitory strength against E. coli PDHc-E1. It exhibited that an acceptable electron-withdrawing substituent in the 4-position of the benzene ring was useful for the binding interaction with the active region of PDHc-E1. The introduction of replacement R in the 4-position of the benzene ring could dramatically raise both enzyme inhibition and antifungal property compared with R in other situations or no substituent on the benzene ring (Figure 69).

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Ren et al. [135] described a successful protocol for direct ortho-C-H alkoxylation of 1,4-di-substituted 1,2,3-triazoles utilizing alcohol as the alkoxyl source. Furthermore, alkoxylated products exhibited potent antifungal activity in combating the root-rot disease of Panax notoginseng (Figure 70).

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A new 4-(1-phenyl-1-hydroxyethyl)-1-(o-hydroxyphenyl(-1H-1,2,3-triazole was designed by integrating the constructional properties of triazole PITENIN anticancer factors and the azole class of antifungal drugs. Their evaluation of a wide spectrum of human fungal pathogens resulted in the identification of several possible antifungal strains, some of which demonstrated stronger antifungal activity than standard drug against Aspergillus fumigatus, Candida glabrata, Cryptococcus neoformans, and Aspergillus niger. Many of these compounds demonstrated strong antifungal activity against several of the examined pathogen. Compounds 138d and 138e were the most effective against all fungal infections, with MICs ranging from 4 to 32 μg/mL. Compounds 138i, 138j, 138f, 138g, and 138h displayed very good antifungal activity excluding A. niger (MIC > 128 μg/mL) as shown in Figure 71. Surprisingly, all derivatives exhibited greater activity than Fluconazole against Candida glabrata NCYC 388. In general, dichloro- or bis-trifluoromethyl groups on the scaffold are expected to enhance lipophilicity while simultaneously polarizing the sample molecule [136].

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A series of novel strobilurin derivatives with various 1,2,3-triazole side chains were synthesized. As shown in Figure 72, all of the compounds were evaluated in vitro for fungicidal activity against Phytophthora capsici, Alternaria alternate, Gibberella zeae, Sclerotinia sclerotiorum, and Botrytis cinerea, with some displaying medium-to-high fungicidal activity against Alternaria alternate and Phytophthora capsici. Difenoconazole was used as a standard medicine. Amid the goal compounds X = Br and R = 4-OCH₃, R = 4-CH₃ was preferred for the advancement of antifungal activities, which were surprisingly better than 139e (R = 3-NO₂) and compounds including (X = Cl) with different halogen atoms on the benzene ring displayed comparable inhibition rates against the examined fungi, for example, 139f, 139g, and 139b [137].

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Pyta et al. [138] used the click reaction to enhance the antifungal agent gossypol by adding a triazole moiety. The biological assessment of the new gossypol-triazole conjugates, as shown in Figure 73, revealed that the potency of 140g and 140h compounds containing triazole-benzyloxy portion was equivalent to that of conventional medication against Fusarium oxysporum. Antifungal tests were applied on some plant pathogens that cause serious difficulties in agriculture. In microbiological investigations, compounds 140a–f, as well as gossypol, were found to be ineffective against Aspergillus brasiliensis.

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A new series of 1,2,3-triazole phenylhydrazone derivatives were synthesized, and most of the derivatives displayed vigorous activity against F. graminearum, R. solani, and S. sclerotiorum. Compounds 141d–f, 142d, 142e, 143d, and 143e depicted the most excellent antifungal activity against F. graminearum with EC50 values ranging from 0.28 to 1.06 mg/mL. Compound 143d showed the biggest and second most inhibitory activity against R. solani and S. sclerotiorum with EC50 values of 0.86 and 1.66 mg/mL, respectively. When comparing all compounds with similar halogen substituents, it has an unfavorable effect on antifungal activities, since the methylene group is found among the 1,2,3-triazoles and aromatic rings (Figure 74) [139].

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Santos et al. [140] tested nine synthetic 1,2,3-triazole derivatives against four Candida spp. strains of clinical significance like C. tropicalis, C. parapsilosis, C. krusei, and C. albicans. The two compounds displayed antifungal activity containing 144d against C. tropicalis (MIC > 64 μg/mL) and 144b against C. albicans (MIC = 8 μg/mL) with some stereoelectronic properties allied to the activity. When compared to compounds 144a and 144b, the existence of an aldehyde group in place of alcohol in compound 144c was not desirable for antifungal activity, since compound 144b with methanol as a substituent showed antifungal activity, while compound 144c with aldehyde did not (Figure 75).

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Structure-based design was used to create a novel derivative of 5-substituted benzotriazole as inhibitors of fungal cytochrome P450 lanosterol 14-a demethylase in response to the demand for new antifungal medicines with better potency and a broader range of activity. The antifungal assessment was performed on the fungus Candida albicans (ATCC 10231). At concentration of 100 μg/mL, compounds 145a and 145b displayed larger antifungal activities as compared to the standard drug Fluconazole (Figure 76) [141].

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Phosphonates, quinones, and azoles are examples of drugs found in bioactive compounds. In 3-4 steps, a series of phosphonates linked to quinones and azoles with changing carbon chain lengths were prepared to be in high yield. The antifungal activity of these azole derivatives against the phytopathogenic fungus Fusarium graminearum was found to be extremely high in ethyl preserved phosphates. Free-base phosphates have great antifungal training toward Candida albicans and Aspergillus flavus which are human pathogenic fungi. In terms of cytotoxicity and antifungal activity, compound 146f is the most active with the smallest cytotoxicity, followed by 146d and 146e (Figure 77) [142].

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3. Conclusion

1,2,3-Triazole-hybrids with broad antifungal activity have garnered worldwide attention. This lead compound will act as a potent drug candidate in the future. The CuAAC reaction for the regioselective synthesis of 1,2,3-triazole-hybrids has been proven to be an excellent tool in organic and medicinal chemistry. Fungal infections have a big challenge on the global health system. Fungal infections were the primary cause of death for more than 1.35 million people globally. Treatment of this type of infection is complicated owing to the toxic side effects of antifungal medications; on the other hand, since drug resistance in chemotherapy is one of the most significant hurdles in fungal treatment, the development of novel antifungal agents is critical. The present review explains the recent advantage of 1,2,3-triazole-hybrids as an effective antifungal agent and the mechanism of action and then it evaluates the structure-activity relationship. The versatile synthetic applicability and antifungal activity of these N-heterocycles will aid medicinal chemists in organizing, planning, and executing new drugs with higher activity and lower toxicity.

Ethical Approval

This research has been ethically approved (IR.FUMS.REC.1400.012).

Authors’ Contributions

EZ designed, wrote, and finalized the manuscript and supervised. The first draft of the manuscript was written and revised by MM. Also, MF, ZK, AS, and AK helped in writing and revising the manuscript. All authors approved the final manuscript.

Acknowledgments

The authors wish to acknowledge the support of Noncommunicable Diseases Research Center, Fasa University of Medical Sciences (Grant no. 99289).

Glossary

Abbreviations

AmB:Amphotericin B

CAI:Carboxyamidotriazole

CAP:Community-acquired pneumonia

CCP:Colletotrichum capsici pathogens

[Cp∗RuCl]:Pentamethylcyclopentadienyl ruthenium chloride

CPP:Cotton physalospora pathogens

CuAAC:Copper-catalyzed azide alkyne cycloaddition (CuAAC)

DFT:The density functional theory

DHA:Dehydroacetic acid

DNA:Deoxyribonucleic acid

EC50:Effective concentration

FLC:Fluconazole

HIV-1:Human immunodeficiency virus type 1

HOMO:Highest occupied molecular orbital

IC₅₀:Inhibitory concentration

ITC:Itraconazole

LUMO:Lowest unoccupied molecular orbital

MIBK:Methyl isobutyl ketone

MIC:Minimum inhibitory concentration

MRSA:Methicillin-resistant Staphylococcus aureus

PITENIN:Anticancer agent

RNA:Ribonucleic acid

RT:Reverse transcriptase

RuAAC:Ruthenium-catalyzed azide-alkyne cycloaddition

SAR:Structure-activity relationship

SIV:Simian immunodeficiency virus

TBDMS:Tert-butyldimethylsilyl

TEM-1 and SHV-1:Class A-lactamases commonly found in Escherichia coli and Klebsiella pneumoniae pathogens responsible for urinary tract, respiratory tract, and bloodstream infections

TSAO:Tertbutyldimethylsilylspiroaminooxathioledioxide

VCZ:Voriconazole.

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