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)

A pharmacophore system has been found as 1,2,3-triazole, a five-membered heterocycle ring with nitrogen heteroatoms. ,ese heterocyclic compounds can be produced using azide-alkyne cycloaddition processes catalyzed by ruthenium or copper. ,e bioactive compounds demonstrated antitubercular, antibacterial, anti-inflammatory, anticancer, antioxidant, antiviral, and antidiabetic properties. ,is heterocycle molecule, in particular, with one or more 1,2,3-triazole cores has been found to have the most powerful antifungal effects. ,e 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. ,is review will be useful in a variety of fields, including medicinal chemistry, organic chemistry, mycology, and pharmacology.


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. e core has a substantial impact on biological activity [3]. e 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]. ere 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 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 1,2,3triazole derivatives have been generated and evaluated for antifungal activity in the last few years, with some potential activity against different fungi. is 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. e process of selecting publications for this review is reported in the diagram below ( Figure 1).
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. e 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).
is 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 1,5substituted and 1,4-substituted regioisomers [20].

Mechanism of the Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC).
e reliable click reaction, coppercatalyzed azide-alkyne cycloaddition (CuAAC), has been expanded in medicinal and organic chemistry [25]. In this method for preparing Cu(I) in solution, in situ reduction of CuSO 4 ·5H 2 O by sodium ascorbate was performed in 1,2,3-triazole of water/alcohol (MeOH, EtOH, or BuOH) mixtures. e product was separated by easy purification without the use of chromatography (Scheme 5) [26]. e 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. e 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. e intermediate copper metallacycle is then prepared. e 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].

Mechanism of the Ruthenium-Catalyzed Azide-Alkyne Cycloaddition (RuAAC).
e researchers confirmed that pentamethylcyclopentadienyl ruthenium chloride [Cp * RuCl] complexes may be used as effective catalysts in the reaction of terminal alkynes with azides, resulting in 1,5disubstituted 1,2,3-triazoles (Scheme 7) [28]. e 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. e initial carbon-nitrogen bond is formed between the terminal nitrogen of alkyne and azide in the next step. e product 1,2,3-triazole is then formed by reductive elimination [28].

Synthesis and Structure of 1,2,3-Triazole-Based Marketed
Drugs. Only a few 1,2,3-triazole-containing hybrids have been developed as therapeutic agents in the medicine industry in recent years, with a wide range of pharmacological applications.

General Synthetic Pathway for the Preparation of Pharmaceutical Drugs Containing 1,2,3-Triazole
(1) Synthesis of Tazobactam. Tazobactam is a pharmaceutical that inhibits the bacterial activity of β-lactamases, particularly those attached to the SHV-1 and TEM groups. In other words, it is a substance that can be added to some antibiotics to make bacteria more vulnerable to antimicrobial resistance. Tazobactam is coupled with the broad-spectrum β-lactam piperacillin antibiotic to form the drug piperacillin/ tazobactam, which is used to treat Pseudomonas aeruginosa infections [34]. is medication was developed in 1982 and used in medicine for the first time in 1992. It is a combination of a penicillin and a sulfone [35].
Micetich et al. [36] described a novel route to the synthesis of Tazobactam, which resulted in the cycloaddition of the synthetic intermediate 1 with acetylene gas 2 in water and the dissociation of 1. Finally, the reaction in MIBK without the excess sodium ascorbate supported Tazobactam yields ranging from 4 to 91% (Scheme 10).

Journal of Chemistry
(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]-2oxo-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][39][40]. e 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].
(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 7position by free or substituted α-aminophenylacetamido. ey are synthesized by combining a 3-acetoxymethyl ring to a mercaptoheterocycle. Antibacterial factors are found in products (Scheme 14) [51].
(5) Synthesis of Tertbutyldimethylsilylspiroaminooxathioledioxide (TSAO). TSAO reported a completely novel class of HIV-1-particular factors in 1992 [52][53][54][55][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. ey are designed to interact with RT-virus encoding at a nonsubstrate binding position [57,58]. e 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]  synthetic compounds that include one or more azole rings with three nitrogen atoms in a five-membered ring (as antifungal triazoles) ( Figure 2). In general, azoles have become a more important antifungal drug, since they are less toxic than Amphotericin B (AmB), act against different types of fungi, and have clinical effects in many cases. By inhibiting the fungus cytochrome P-450 3A-dependent enzyme lanosterol 14-alpha-demethylase, the antifungal azoles disturb the conversion of lanosterol to ergosterol [64]. e conversion of lanosterol to ergosterol, which is used in cell wall synthesis, is one of the important functions of this enzyme. e essential nitrogen of the azole ring binds firmly to the Journal of Chemistry fungus cytochrome P450 hemiron in this mechanism, preventing the bond between the substrate and oxygen. Accumulation of sterols, alteration of permeability, and dysfunction of membrane proteins are the result of 14αdemethylase inhibition. e inhibitory pathway of ergosterol biosynthesis is shown in Scheme 16 [65]. 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. e addition of broadspectrum triazoles provides physicians with more effective and less toxic alternatives to Amphotericin B [67].  Figure 3, Compounds 39a, 39b, 39c, 40a, and 40b showed a high antifungal activity compared with Miconazole [68]. 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).

Review of the Latest Papers in the
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].
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].
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. e fungicidal property assessed the impact of five human pathogenic fungal strains, like Candida albicans, Aspergillus flavus, Aspergillus niger, Fusarium oxysporum, and Cryptococcus   F   NH2 cbZ-Cl, NaHCO 3 , 0°C, 2.5h , 2 h 2 ) Rg l y c i d y l b u t y r a t e , r t , 1  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 (R 2 � Cl) and 46d (R 3 � F) displayed equivalent effectiveness against the fungal strain A. niger. e addition of a triazole ring to coumarin increased the antifungal activity of the synthesized compounds. e addition of a triazole ring to coumarin improved the antifungal activity of the synthesized compounds.
Gondru et al. [73] developed a new series of triazolethiazole hybrids using the multicomponent reaction approach. In vitro antimicrobial activity investigations were evaluated. e 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). e 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-  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]. 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 NaHCO 3 -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). 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.
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. e antifungal activity of combination 58h (R 1 � OCH 3 ) 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,  The Compounds 40a and 40b having CH 3 and Cl groups at ortho situation of the phenyl ring showed an great antifungal properties against all the fungal strains The Compounds 39a,39b respectively with having CH 3 group at ortho and para situations of the phenyl ring and compound 39c with Cl group at ortho position exhibited an equal or twice more powerful than Miconazole against all the fungal strains 1,2,3-triazole motif compounds 58g and 58h revealed significant activity among all synthesized triazoles [79].

1,2,3-Triazole-Amide
Hybrids. González-Calderón et al. [80] used a one-pot method to synthesize new benzylic 1,2,3-triazole-4-carboxamides with passable yields. As shown in Figure 15, the sequence of compounds was evaluated for antifungal activity in vitro toward four filamentary fungi and four Candida species. Compounds 59b and 59c were the most impressive fungal factors (of all the trial compounds) against R. oryzae, even better than the standard medicine (MIC � 0.017 μmol/mL for 59b and 59c; MIC � 0.14 μmol/mL for Itraconazole). e SAR for compounds 59b and 59c showed that the 4-phenyl-4-carboxamide triazole was accountable for the antifungal result, Presence of F and OCH 3 groups on coumarin increased antifungal activity OCH 3 group of the triazole compounds (41g and 41h) displayed weak activity Presence of the 1,2,3-triazole moiety showed more activity than the intermediate Coumarin Quinolinone e results of anti-fungal activities disclosed that OCH 3 and Cl substituted coumarins 42a and 42b) were realy active against yeast strains.
The compound 45b containing chlorosubstituent at meta situation of phenyl ring exhibited favorable activity as compared to the reference drugs Miconazole and Amphotericin B.
Compound 46d containing fluoro-group at para situation of phenyl ring has been showed good stopper of C. albicans with MIC amounts 12.5 µg/mL and double active as compared to the Miconazole and similar to Fluconazole.
Compounds with (chloro-group at para, meta and ortho), and 46e with MIC amounts 25 µg/mL displayed equal power for fungal strain C. albicans compared to the Miconazole.
Most of the compounds were inactive against the fungal strain A. niger, A. flavus and C. neoformans The compound 48d (6-bromo-8-methoxycoumarinyl; MIC, 5.9 µM) was found to be a very strong hybrid of the examed sequence against most of the Candida spp when compared to Miconazole (MIC,18.7 µM).
The compounds 48a and 48b dis-played antifungal activity against C.albicans MTCC 854 and Issatchenkia hanoiensis MTCC 4755 at MIC amount of 7.1 µM and 6.5 µM in order that is smaller than the reference drug.
48a: R 1 = R 2 = R 3 = H 48b: R 1 = H, R 2 = R 3 = C 4 H 4 48c: R 1 = OCH 3 , R 2 = R 3 = H 48d: R 1 = OCH 3 , R 2 = Br, R 3 = H 48e: R 1 = R 2 = NO 2 , R 3 = H while neither the electron-wealthy ring (including piperonyl in 59c) nor the electron-needy ring (substituted with 2,6-dichloro to form 59b) was related. Compounds with the largest functional groups in their structure exhibit lower activity than standard drug, indicating the need for a modest substituent in positions 1 and 5 of triazole to interact positively with the active site of the fungus. 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].
Kaushik et al. [82] reported a novel library of 1,2,3triazoles 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). e use of [Et 3 NH][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. ese 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].  14 Journal of Chemistry 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 Chromone ring Compound 51a with dichloro replacement and compound 51b with Cl, CH 3 substituent showed that the compounds with more electron donating groups are accountable for the increased activity of the compounds.

Flavone moiety
The flavone compounds having difluoro substituted phenyl rings were found to be slow versus antifungal and also antibacterial activity. is utilized as standard medicine. Most of the compounds showed moderate-to-great antifungal activity ( Figure 19).
Yan et al. [85] The therapy with 59d and 59e led to a very restricted affect on A. fumigatus.
There was no structure-activity relationship for the yeast growth inhibition of C. albicans compled by the active compounds.
Little ethers as substituents meliorated the outcomes obtained, as proofed by the information for 59a and 59c. Other serious facet is the size of the structure. the positive control. e 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-OCH 3 ), 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-OCH 3 ) ( Figure 20).
Brahmi et al. [86] explored a novel sequence of semicarbazone-triazole hybrid derivatives with condensation among the commercial semicarbazide hydrochloride and heterocyclic aldehydes. e 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. e 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. e following antifungal activity levels were observed: 66c > 66e > 66d against F. oxysporum. 66a and 66b had low-to-moderate activity ( Figure 21).
The results showed that compounds having naphthyl moiety revealed premier activity in comparison to phenyl moiety. Kaushik and Luxmi [87] examined a collection of 25 amides linked to 1,4-disubstituted 1,2,3-triazoles. e 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).
Amide-ester-connected 1,4-disubstituted 1,2,3-triazoles were synthesized by employing Copper(I)-catalyzed 1,3dipolar 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 NO 2 group showed great antifungal activity against all the strains compared to H and OCH 3 groups Compounds 62a and 62b were the most active in the sequences as they owned a NO 2 group at R and Cl groups at R 2 and R 3 ; the Cl group at the R 1 situation for 62c consequenced in small activity against one fungal strain. The CH 3 group at the R 1 /R 2 /R 3 position and the NO 2 group at the R position in 62d, 62e, and 62f resulted in good activity than that of the others in the sets.  fungus strains, Aspergillus niger and Candida albicans. e antifungal activity results revealed that most of the synthesized compounds exhibited moderate-to-good antifungal efficacy against the named fungus strains. Compound 69e including R 2 � electron-donating group and R 1 � p-Br-C 6 H 4 -had good antifungal activity against A. niger. R 1 and R 2 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].
e findings revealed that all of the target compounds have notable antifungal activity. Compound 70b showed the most potent antiphytopathogenic activity, with EC 50 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 The outcome was nearly the equal when R 1 was fixed and R was changed 65A1-4 (3,4-di-Cl), 65A2-1 and 65A3-1 exhibited the most principal antifungal activities between compounds in sequence A.
Benzene ring substituted at the 4-position of 1,2,3-triazole showed higher activity than benzo ring and aliphatic chain.  chosen to experiment antifungal property in vivo despite the equal antifungal activity produced by other compounds. e EC50 values displayed that an electron-withdrawing group outperformed an electron-donating group for R 2 ( Figure 25).
A series of 5-nitrofuran-triazoles were synthesized with appropriate structural corrections of the formerly reported The existence of electron withdrawing group, i.e. nitro showed good antifungal yield while naphthyl group on nitrogen atom of amide linkage exhibited powerful antifungal activity.
Triazoles including thienyl (C 4 H 3 S) moiety showed good activity in case of A.niger in analogy to furyl (C 4 H 3 O) moiety.
Triazoles containing thienyl and nitro group showed notable antifungal yield in comparison with the reference drug. All the examed compounds with Br and NO 2 group on phenyl ring exhibited good antifungal activity against both the strains.
The existence of the alkyl group on carbon having free hydroxyl group enhanced the antifungal activity against A. niger and C. albicans.  Antifungal activity experiments showed that 70a performed better than 71a and 72a R 2 Halogen substituents of R 1 at the ortho situation and halogen substituents of R 2 at the para position (70b, 70c, 70d and 70e) created the optimal combinations. derivative containing 1,2,3-triazolium and pyridinium increased antifungal activity as compared with chitosan and chitosan derivations bearing 1,2,3-triazole and pyridine. All of the synthesized compounds displayed superior ability of inhibiting the growth of the examined phytopathogenic fungi than chitosan ( Figure 28).
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). e inhibitory indices of six chitosan derivatives 77 were greater than those of unmodified chitosan and quaternary ammonium chitosan 76 at the identical concentration. e results revealed that the triazolyl group linked to the synthesized chitosan derivatives contributed significantly to antifungal action, hence increasing their antifungal activity ( Figure 29).
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. ese 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).
A novel group of inulin derivatives with 1,2,3-triazoliumcharged 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].
Li et al. [99] investigated three new chitosan derivatives, including 1,2,3-triazole with or without halogen. eir antifungal activity toward three kinds of phytopathogens was evaluated via hyphal mensuration in vitro. e 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).

1,2,3-Triazoles-Pyrazole, Imidazole, and Benzimidazole
Hybrids. Among the heterocycles containing nitrogen, imidazole, pyrazole, and triazole have many biological, Compounds showed great antifungal activity versus all the examed fungal strains denoting no remarkable effect of substituents on the activity.
The 1,2,3-triazolium would be a more impressive anion captor than triazole after quaternarization, that may help fixate the free radicals figure. The results showed that increasing the length of the alkyl chain on the 1,2,3-triazolium rings reduced the antifungal activity of starch derivatives (P < 0.05) against all the fungi strains and the antifungal activity increased respectively: 83a > 83b > 83c > 83d > 82a ~ 82d > starch. Six hybrids (85a-f ) (MIC � 0.0246-0.0282 μmol/mL) were found to have remarkable influence on C. albicans. e research showed that triazole derivatives with OMe and Cl groups at the anilide ring had better antifungal activity than NO 2 . Among the synthesized compounds, most of the methyl derivatives in the pyrazole ring had higher activity than the H analogs. In general, these compounds have been shown to be more effective against A. niger than against Candida albicans [100].
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. e 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).
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).
Dubovis et al. [105] designed and developed a novel and fundamental method for synthesizing 1-(1H-imidazole-4yl)-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.
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 The outcomes showed that the chitosan derivatives with powerful electronwithdrawing valency dis-played greater antifungal activity.
This study offeres that the synergistic affect of halogens and triazole will enhance the antifungal activity of chitosan derivatives.  The compounds 87a, 87b, 87c, 87d, and 87e exhibited high antifungal activity with lower MIC≤25 µg/mL.  Journal of Chemistry Compounds 88a and 88b bearing 4-chloro phenyl and 2,4-dinitro phenyl substituents in the 2nd situation of the pyrazole ring, respectively, were showed to be more powerful antifungal agents than the other compounds.  inhibition toward all of the tested fungal strains that were more powerful than the standard drug Fluconazole.
e fungicidal activities of all the collected compounds against cotton physalospora pathogens (CPP) and Colletotrichum capsici pathogens (CCP) were evaluated, and the results displayed that these compounds, mainly 99a and 99f, exhibited remarkable inhibitory effects for fungi. Compounds revealed greater activity toward CCP than toward CPP (Figure 44).
Soltani Rad et al. [110] described a new class of fungicidal compounds known as 1,2,3-triazolyl β-hydroxy alkyl/carbazole hybrid molecules. e '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).
Sakly et al. [113] investigated a wide range of novel functionalized spirooxindole-pyrrolidine and spirooxindole-pyrrolizidine-connected 1,2,3-triazole conjugates. e 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).
Aouad [114] reported the discovery of new isatin-1,2,3triazoles 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. e isatin-1,2,3-triazole hybrids including a piperazine unit were found to be the most active of Fluorinated Schiff bases were found more impressive against all of the examed fungal strains.
Especially, the Schiff base 93a containing a CF 3 group applied the greatest antifungal inhibition activity. The outcomes legibly showed that the existence of electron withdrawing groups on phenyl ring increased the antifungal activity of synthesized compounds against A.niger.

2-mercaptobenzimidazole
Presence of electron donating groups on phenyl ring raised the antifungal activity of synthesized triazoles against C. albicans.
The attendence of aliphatic side chains displayed more adequate result in comparison with aryl sections even bearing various substituents. Journal of Chemistry 29 the examined compounds (108a-c). Compounds with a piperazine moiety (109a-c) displayed the biggest antifungal inhibition activity (Figure 49). Shaikh et al. [115] described novel triazole-based isatin derivatives that were evaluated for biological activity using click chemistry. e 1,2,3-triazole-based isatin compounds showed good-to-moderate activity against all five human pathogenic fungal strains tested. e activity of 110b and 110c with chlorogroup 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).

1,2,3-Triazole-Quinoline Hybrids.
Nesaragi et al. [116] described a new sequence of quinolin-3-yl-methyl-1,2,3triazolyl-1,2,4-triazol-3(4H)-ones synthesized via click chemistry as a final tactic in which azides with final alkynes were tested for antifungal properties against four various pathogenic fungi (C. albicans, A. flavus, A. fumigatus, and A. niger). Fluconazole was employed as a standard drug. e antifungal results of synthesized derivatives announced favorable activity. According to the in silico and in vitro studies, these additional quinolines triazoles may acquire the arbitrary structural prerequisites for secondary synthesis of novel restorative components ( Figure 51).

Ar Ar
In total, compound (103a) also showed great broad-spectrum fungicidal activity against all the examed fungi.
102a: Ar = phenyl; 102c: Ar = 3, 4, 5-trifluorophenyl 102b: Ar = 4-trifluoromethylphenyl; 103a: Ar = 3, 4, 5-trifluorophenyl Dispir ooxind ole-py rrolizi dine linked triazol es Disp iroo xind olepyrr olid inelink ed triaz oles Compounds owning a NO 2 group at the triazole ring such as 106b and 107b also 106c and 107c including a CH 3 group at the triazole unit were very active against C. albicans with respect to the standard antifungal factor griseofulvin. 106 107 With the presence of halogen substituents on indolinone and some substituentson the aryl ring of the triazole have been increase the antifungal activity of compounds.  Compounds 110a for Aspergillus flavus, with nitro-group at para, 110b with chloro-group at meta, and 110e with fluoro-group at para position of phenyl ring displayed comparable activity as compared with reference drug.
Compounds 110d and 111a containing nitro-substituentat meta situation of phenyl ring displayed favorable activity as compared with the Miconazole.

Journal of Chemistry
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). e results of anticandidal activity were obtained from three various Candida strains. ey showed that compound 114a outperformed Fluconazole with IC 50 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 IC 50 values, demonstrating the nontoxic treatment of these inhibitors ( Figure 53).

bis-Triazole Derivatives.
Novel series of bis-1,2,3-and 1,2,4-triazoles as potential antimicrobial agents were synthesized by Bitla et al. [119] also, and all of them screened for their antifungal effect against Saccharomyces cerevisiae and Aspergillus niger.
e majority of the synthesized compounds displayed favorable antifungal activity with the zone of inhibition (1.5-8.2 mm). e studies showed that (115a-d) compounds displayed an impressive antifungal effect among all the other synthesized compounds (Figure 54). e click reaction catalyzed by Cu(I) used a class of 1,2,3triazole containing oxime products under both conventional and microwave irradiation conditions. e 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].
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]. e 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).
Pertino et al. [123] synthesized 24 novel triazole derivatives from the abietane diterpenes carnosic acid and carnosol through using click chemistry. e length of the linker and the substituent on the triazole portion differed among compounds. e 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-Brbenzyl 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 (R 1 : p-bromobenzyl), the existence of a Br in the aromatic ring did not shift the activity until the length of the linker was three CH 2 units; however, it decreased when the linker possessed two CH 2 units. Comparing the activities of 122a and 122b with those of 122e and 122f, introducing a nitro group in the aromatic ring (R 1 : pnitrobenzyl), the activity of the nitro compounds is lower ( Figure 58). Figure 59, a series of novel derivatives of 1-(4-methyl-2-aryl-1,3-thiazole-5yl)-2-(4-aryl-1,2,3-triazol-1-yl) ethanol were synthesized and their antifungal properties screened in vitro against Candida albicans, Aspergillus niger, Rhodotorula glutinis, and Penicillium chrysogenum. Most of the compounds have moderate-to-good antifungal activity against A. niger in comparison to the standard medicine Ravuconazole [124].

1,2,3-Triazole Linked to Other Heterocyclic Pharmacophores. As it is shown in
otla 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).
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).
Seventeen new benzoxazole derivatives, containing a 1,2,3-triazole scaffold, were generated in order to discover contemporary bioactive compounds with outstanding antifungal properties. e antifungal activities of the synthesized compounds were screened toward Fusarium verticillium (FV) and Botrytis cinerea (BC), with hymexazol serving as a positive control. e 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). e compounds were more active against BC than against FV (Figure 62) [127].  The raised anticandidal activity of compounds 114a and 114b might be happened owing to existence of quinoline ring and free aldehyde group, in order along with 1,2,3 triazole ring in their buildings. The compounds including OCH 3 substituents displayed good activity compared to else compounds. Straight and adaptive azide-enolate (3 + 2) cycloaddition was used to synthesize modern oxazolidin-2-oneconnected-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). e 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].
González-Calderón et al. [129] reported the first synthesis of a new kind of compound, using 1′-homo-N-1,2,3-triazolebicyclic carbonucleosides 129a and 129b that exhibited good activity against some of the yeast strains examined (Figure 64). e new benzofuran-triazole hybrids were generated using click reaction. e antifungal effect of goal compounds toward five strains of pathogenic fungi was assessed using the microdilution broth technique. e 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. e primary SARs were supported by the

Miscellaneous 1,2,3-Triazole Hybrids.
Yadav et al. [131] synthesized novel fluorinated-chalcone-1,2,3-triazoles. e antimicrobial assessment revealed that most of the compounds displayed unusual activity. When 1,2,3-triazole and chalcone were added to the antimicrobial screening results, the activity increased. Compound 131c containing pnitro group displayed superior power against A. niger and C. albicans with MIC value of 0.0032 mmol/mL compared to Fluconazole (MIC � 0.0102 mmol/mL). Compound 131b with a bromine group demonstrated comparable activity to the standard with MIC values of 0.0054 mmol/mL against C. albicans. Compounds having nitro and methoxy groups on the benzene ring displayed better activity against most of the microorganisms tested ( Figure 66).
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 Compounds 121a, 121b, 122b and 123a, that displayed the best activities against C. albicans, containing the following usual properties: 1: the linker to the diterpene part included three CH 2 units. 2: in the triazole rings, R 1 was either a methyl phenyl sulfide (compounds 121a and 123a) or a benzyl (compounds 121b and 122b); 3: the activity was nearly the identicalfor the four compounds 4: when R 1 connected to the triazole ring was p-bromobenzyl or p-nitrobenzyl, the equivalent derivatives were passive.
For compound 121a and 121b the γ-lactone emerges to be significant for activity.
The outcomes showed some selectivity for the various fungi and that the assignment of the lactone is serious for the effect.   He et al. [134] investigated the activity of 5-iodo-1,4disubstituted-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 (IC 50 � 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. e 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. e 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).
Attenting the antifungal assay outcomes, it can be datumed that the derivatives with a di-fluorine substituted phenyl ring at the benzofuran C-2 side chain are more impressive than the mono fluorine ones (e.g., 130d vs. 130f). The substituted groups on the phenyl ring connected to the triazole also had an effect on the activity.
The alkyl-substituted compounds are more powerful than the halogenated derivatives (e.g., 130c vs. 130d) and the ortho-substituted derivatives are stronger than the para isomers (e.g., 130e vs. 130d). Screening results showed the increasable effect of activity when that 1,2,3-triazole and chalcone are attached.

Journal of Chemistry 39
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-OCH 3 , R � 4-CH 3 was preferred for the advancement of antifungal activities, which were surprisingly better than 139e (R � 3-NO 2 ) 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].
Pyta et al. [138] used the click reaction to enhance the antifungal agent gossypol by adding a triazole moiety. e 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 When 4-CO 2 Et as R was presented into the benzene ring, both activities of compound 139b notably reduced.
For the di-substituents, R = 3-CH 3 -4-Cl or R = 2-Cl-4-NO 2 was most useful to both antifungal activity and enzyme inhibition.  agriculture. In microbiological investigations, compounds 140a-f, as well as gossypol, were found to be ineffective against Aspergillus brasiliensis.
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].
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. e 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).
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  The antifungal activity for many of compounds was not remarkable when there was no substituent on the left side aromatic ring.
The presence of a halo-substituent on aryl ring, forexample 138a, 138b etc, showed modest progress in the antifungal activity.
The presence of two trifluromethyl groups on this aromatic motif (that are chief in case of the PITENIN analogues), displayed great antifungal activity.
When two Cl and F atoms were sited on this ring, like 138c and 138d, antifungal activity revealed notable increase In the azido portion of the structure,the activity modified from no substitution<5-fluoro<4-chloro<5-chloro with respect to -OH. e 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].
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. e antifungal activity of these azole derivatives against the phytopathogenic fungus Fusarium graminearum was found to be extremely high in ethyl preserved phosphates. Freebase 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]. Influence of the substituent X (Br or Cl) on the antifungal activity for all test fungi, showed nearly identical power,like the inhibition speeds of compounds 139a and 139b against P.capsici were up to 69.1%, 139c and 139d for A. alternate were 61.3% and 69.0%.
The inhibitory rates of 139h (R = 3-NO 2 ) and 139d (R = 4-CH 3 ) against P. capsici were 69.1% and 55.5%, and against A. alternate were 53.6% and 69.0% in series and the inhibition rate of 139h was 69.1% against P. capsici, that was better than 139i (R = OCH 2 Ph).  Presentation of triazole-benzyloxy section to gossypol skeleton amended antifungal activity of compound 140g, against to its antibacterial power.
The synthesized compounds 140a-140h displayed the greatest activity against Fusarium spp. strains, with the exclusion of F.acuminatum.
The most compelling results were recieved for Fusarium spp. All the compounds (n = 0 or n = 1) with halogen substituents of R 3 at the para position, particularly for p-F and p-Cl, display remarkable results and the stronger the electron withdrawing potency of the R 3 substituent, the higher the activities.
When n = 0, comparing the all compounds (141~143), methyl substitution at the R 1 or R 2 positions has no notable results on antifungal activity,whiles when n = 1,methyl substitution seems have an effect on activity, but there is no clear tendency. Compounds (with the ester group in lieu of aldehyde or alcohol) the existence of the nitro group was super for antifungal activity at least for one of the strains.

N HN
The other substituents like methyl, cyano, iodine, bromo and methoxy were not desirable for the antifungal activity.
The derivative with NO 2 group at para situation (144d) was active, while NO 2 group at meta position was inactive. On doing SAR study it was seen that all 5-substituted phenylaminomethyl or phenoxymethyl derivatives of benzotriazole displayed powerful activity against C. albicans as compared to Fluconazole. Hence, 5-substitution with phenylaminomethyl or phenoxymethyl side chain is needful for protecting the power of benzotriazole derivatives.

Conclusion
1,2,3-Triazole-hybrids with broad antifungal activity have garnered worldwide attention. is lead compound will act as a potent drug candidate in the future. e CuAAC reaction for the regioselective synthesis of 1,2,3-triazolehybrids 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. e 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. e 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.  The collation of MICs and IC50 showed that with longer carbon chain length among phosphonate and anthraquinone analogs consisting of azole and quinone moieties (146a-146f) raises antifungal activity 146 147

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
EZ designed, wrote, and finalized the manuscript and supervised. e 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.