Novel 1, 2, 4-Triazoles as Antifungal Agents

Kazeminejad, Zahra; Marzi, Mahrokh; Shiroudi, Abolfazl; Kouhpayeh, Seyed Amin; Farjam, Mojtaba; Zarenezhad, Elham

doi:https://doi.org/10.1155/2022/4584846

BioMed Research International

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Review Article | Open Access

Volume 2022 | Article ID 4584846 | https://doi.org/10.1155/2022/4584846

Novel 1, 2, 4-Triazoles as Antifungal Agents

Zahra Kazeminejad,¹Mahrokh Marzi,²Abolfazl Shiroudi,³Seyed Amin Kouhpayeh,⁴Mojtaba Farjam,^2,4and Elham Zarenezhad²

Academic Editor: Abdelfatteh El Omri

Received21 Dec 2021

Accepted03 Mar 2022

Published22 Mar 2022

Abstract

The development of innovative antifungal agents is essential. Some fungicidal agents are no longer effective due to resistance development, various side effects, and high toxicity. Therefore, the synthesis and development of some new antifungal agents are necessary. 1,2,4-Triazole is one of the most essential pharmacophore systems between five-membered heterocycles. The structure-activity relationship (SAR) of this nitrogen-containing heterocyclic compound showed potential antifungal activity. The 1,2,4-triazole core is present as the nucleus in a variety of antifungal drug categories. The most potent and broad activity of triazoles have confirmed them as pharmacologically significant moieties. The goal of this review is to highlight recent developments in the synthesis and SAR study of 1,2,4-triazole as a potential fungicidal compound. In this study, we provide the results of a biological activity evaluation using various structures and figures. Literature investigation showed that 1, 2, 4-triazole derivatives reveal the extensive span of antifungal activity. This review will assist researchers in the development of new potential antifungal drug candidates with high effectiveness and selectivity.

1. Introduction

Heterocyclic organic chemistry is a main field in organic and medicinal chemistry [1–4]. Azoles are nitrogen-containing five-membered heterocyclic compounds [5, 6]. The presence of nitrogen in heterocycles has a major effect on biological activity. Recently, azole compounds have become hot topics around the world [2, 7]. Among the azoles fused as heterocyclic compounds, 1,2,4-triazole derivatives with molecular formula (C₂H₃N₃) are the most stable compounds [8]. 1,2,4-Triazoles showed broad ranges of biological activities, such as antimalarial [9], antiurease [10], antiviral [11], anticonvulsant [12], antioxidant [13], and antifungal [14]. Some of the medicinal plants containing triazole scaffolds were demonstrated to be antifungal agents, including cyproconazole, triadimefon, metconazole, tebuconazole, propiconazole, epoxiconazole, and prothioconazole [15]. Annually, invasive fungal infections cause 1.7 million deaths in the world, which is a major public health issue [16]. One of the most serious issues is the rise of synthetic drug resistance to various fungal pathogens; thus, the synthesis and development of new 1,2,4-triazoles with low toxicity are essential worldwide [17]. This group of bioactive compounds acts by inhibiting the activity of cytochrome P450-dependent enzyme, the lanosterol 14α-demethylase (CYP51), which is an important enzyme in fungi ergosterol biosynthesis [18]. Azoles link to the iron in porphyrins, causing a blockade of the fungal ergosterol biosynthesis pathway resulting in the agglomeration of 14-demethylated sterols [19]. Recently, novel derivatives of 1,2,4-triazoles were prepared and evaluated for fungicidal activity and some of them showed potential activity against certain fungi. In previous years, many research articles have emphasized the importance of 1,2,4-triazoles as potent antifungal and antibacterial properties [20–31]. However, this review is focused on the latest papers (2015–2021) in the synthesis of new 1,2,4-triazole as an antifungal agent and evaluating structure-activity relationship (SAR) to provide an insight for the logical synthesis of more effective 1,2,4-triazole antifungal candidates. The diagram of choosing publications and the content of this review are illustrated in Figure 1.

2. Synthesis of 1,2,4-Triazoles

1,2,4-Triazoles are five-membered sp² hybridization compounds containing three nitrogen atoms at the 1-, 2-, and 4-positions of the ring. There are two tautomeric forms: 4H-1,2,4-triazole and 1H-1,2,4-triazole (Scheme 1) [32].

2.1. General Pathways

A simple method for preparing 1,2,4-triazoles has been introduced from the reaction of formamide and hydrazines without a catalyst using microwave irradiation (Scheme 2) [33].

A series of 1,3-disubstituted-1,2,4-triazoles were synthesized by reacting amidine and trialkyl amines with K₃PO₄ as a base in the presence of a copper (II) catalyst (Scheme 3) [34].

I₂-mediated oxidative N-S and C-N bond formations are an ecologically friendly and effective approach for synthesizing novel 1,2,4-triazoles from isothiocyanates (Scheme 4) [35].

1,5-Disubstituted-1,2,4-triazoles were prepared using copper (II) as the catalyst. This regioselective method makes it simple to produce 1,2,4-triazole moiety with wide substrate amplitude, high yield, and significant functional group compatibility (Scheme 5) [36].

The synthesis of 1,2,4-triazoles from aliphatic amines and hydrazones has been developed using a cascade C-H functionalization, oxidative aromatization sequence, and double C-N bond formation under iodine as the catalyst (Scheme 6) [37].

2.2. Synthesis by Substitution of 1,2,4-Triazole

2.2.1. Arylation Reactions

Under reflux circumstances in pyridine, 1-aryl-1,2,4-1H-triazole is arylated by an aryl halide with electron-withdrawing groups using CuO as the catalyst (Scheme 7) [38, 39].

2.2.2. Alkylation

When sodium methoxide in methanol is used as the base, 1,2,4-triazole is alkylated at the N1 position, yielding in a mixture of 1-methyl- and 4-methyl-1,2,4-triazole with methyl sulfate alkylation in NaOH (Scheme 8) [40].

2.3. Direct the Synthesis of N4-Substituted Triazoles

A group of 4-Arylsubstituted-1,2,4-4H-triazoles yields via the reaction of N, N-diformylhydrazine with primary amine at high temperatures (Scheme 9) [41]. Pellizzari and Soldi pioneered this system by reacting simple arylamines such as naphthylamine, aniline, or toluidine with N, N-diformylhydrazine [42, 43], as well as downloading via slight changes in amino heterocycles containing 3-amino-1,2,4-4H-triazole to generate 3,4-bitriazoles [44–46].

3. Pharmaceutical Drugs

3.1. Chemical Structures of 1, 2, 4-Triazole-Based Marketed Drugs

Bladin were the first to synthesize 1,2,4-triazoles in 1885 [31]. The primary procedures, such as the reaction of formamide with formylhydrazine, produced low yields of 1,2,4-triazole [47, 48]. Later, it was found that condensation of formamide with hydrazine sulfate yielded 1,2,4-triazole in average yield. Various pharmacological activities of 1,2,4-triazoles as antifungal [42, 49, 50] have been observed which included fluconazole, isavuconazole, itraconazole, voriconazole, ravuconazole, and posaconazole (Figure 2). Several 1,2,4-triazole-based drugs are under clinical use for the treatment of different diseases. Some of the most effective drugs available in the market are described in the following Table 1.

3.2. Structure-Activity Relationship of Fluconazole

Fluconazole is well known as one of the most potent antifungal drugs with remarkable interest in medicinal chemistry. Due to the importance of fluconazole as a reference drug, the structure-activity relationship is shown in Figure 3.

4. 1,2,4 Triazole Scaffold for the Development of Antifungal Agents

This part of the review is classified into two parts based on the structural similarities of 1,2,4-triazole derivatives. First, we explained novel analogues of commercial 1,2,4-triazole drugs and then discussed 1,2,4-triazole-based scaffolds with various functional groups such as indole, benzimidazole, quinolone, quinazoline, amine, hydrazone, amide, sulfur, and oxime ether that showed remarkable antifungal properties, as well as SARs of all synthesized compounds.

4.1. Analogues of Commercial 1,2,4-Triazole Drugs

Most triazole compounds containing 1,2,3-benzotriazine-4-one demonstrated more antifungal activity against Candida albicans and Cryptococcus neoformans than reference drug with MIC values ranging from 0.0156 to 2.0 μg/mL. Furthermore, a strong SAR investigation revealed that derivatives with groups −NO₂ and CF₃ at the 7-position exhibited more effective antifungal activity than derivatives with groups at the 5-, 6-, and 8-positions. In addition, products containing halogens such as Cl and F demonstrated more excellent antifungal activity than those containing electron-withdrawing groups. Meanwhile, compound 1a () demonstrated remarkable antifungal activity specifically against Aspergillus fumigatus () and moderate activity against fluconazole-resistant Candida albicans strains (Figure 4) [88].

Blokhina et al. [29] investigated the fungicidal activity of thiazolo[4,5-d] pyrimidine hybrids with (1H-1,2,4) triazole. All derivatives include the methyl-(2a), fluoro-(2b), and chloro-(2c) substituents at the para position. In vitro evaluation of various compounds with a potent alkylpiperazinyl linker demonstrated antifungal activity similar to the standard drug. The most active compounds are methyl-(2a), fluoro-(2b), chloro-(2c) methyl-(3a), and fluoro-(3b). Based on MIC values, antifungal activity is classified as poor (≥32 μg/mL), modest (16–32 μg/mL), good (4–8 μg/mL), excellent (0.06–2 μg/mL), or outstanding based on MIC values (Figure 5).

Montoir et al. [89] reported a novel class of azole antifungal compounds based on a pyrrolotriazinone scaffold. As a result, these compounds demonstrated fungicidal activity against pathogenic Candida species in vitro (fluconazole susceptible and fluconazole resistant) and were more active than voriconazole against two Candida albicans candidates. Compound 4e also showed promising in vitro activity against several filamentous fungi, including Aspergillus fumigatus (Figure 6).

Xie et al. [90] demonstrated that the entire series of triazole containing isoxazole compounds (5a-f) were antifungal against eight human pathogenic fungi. Compound 5a showed a strong inhibitory activity toward Candida parasilosis and Candida albicans with MIC80 values of 0.0313 μg/mL. According to the SARs study, mono-fluorine on the phenyl ring possesses antifungal activity. On the other hand, enhancing the number of fluorine atoms (5c-d) may result in a reduction in antifungal activity (Figure 7).

In comparison to the reference drugs, voriconazole, fluconazole, and ravuconazole, an alkyne linked in the side chain of the triazole derivatives demonstrated good fungicidal activity against eight human pathogenic fungi, with particularly noticeable activity against Cryptococcus species and Candida. Compounds 6b and 6c shown in vitro antifungal activity against all the investigated fungi with (), which is greater than fluconazole and ravuconazole. SAR study shows that para fluoro (6e, 6h), para chloro (6b), and para cyano (6c) substituted phenylalkynyl, or pyridinyl alkynyl (6m, 6n) side chains improve activity. Compounds with R groups in the para position are shown to be more active than meta or ortho compounds (Figure 8) [91].

The antifungal efficacy of triazole alcohol derivatives toward 16 Candida isolates from five different species, including fluconazole-susceptible and fluconazole-resistant isolates, was investigated. All of these derivatives with MIC values of 0.063–1 mg/mL showed higher activity than fluconazole () against fluconazole-susceptible isolates; significantly, compounds 7b and 7e were also active against fluconazole-resistant species. However, the effect of chloro substitution depends on the type of species. For example, the 2,4-dichloro substituent 7d was shown to be more effective against C. albicans than 3-Cl (7b) or 4-Cl (7c). In the case of C. krusei, however, the 3-chloro group was better than the 4-chloro or 2,4-dichloro substituents. The addition of fluoro or bromo groups to the benzyl residue, however, had no beneficial impact. Among the fluorobenzyl regioisomers (7f-h), the 3-fluoro 7g analog was more active against Candida species (Figure 9) [92].

Chandrika et al. [93] investigated novel fluconazole (FLC) compounds for antifungal activity against the clinical strains of C. parapsilosis, C. glabrata, and Candida with aryl, alkyl, cycloalkyl, and dialkyl-amino substituents for neoformans using MIC determination. The activity of the alkylamino FLC derivatives was shown to be directionally related to the length of the alkyl chains (Figure 10).

Tekale et al. [94] investigated the antifungal activities of triazole compounds, including imidazole. The impact of the imidazole side chain on the in vitro fungicidal activity of novel synthesized compounds toward various microorganisms such as aspergillus, niger, aspergillus fumigates, and Candida albicans was demonstrated. Compound 9e had the lowest activity against C. albicans, and compounds 9b & 9d had higher activity against A. niger than the other compounds (Figure 11).

The MIC₈₀ values of new triazole compounds containing 1,2,3-triazoles or substituted amines as side chain 10a-o derivatives demonstrated better antifungal properties than those of fluconazole on three significant fungal infections except for 10i. Furthermore, the considerable compounds 10d, 10 k, 10n, 10 m, and 10o were reported on the Aspergillus fumigatus strain (MIC₈₀ range: 0.125–1 μg/mL). In addition, 10k can be applied to almost all fungi tested, especially Aspergillus spp. In vitro biological assessments of the compounds 10d and 10k showed potent antifungal properties (Figure 12) [95].

Sadeghpour et al. [96] reported two classes of novel fluconazole-derivatives containing nitrotriazole or 2-(piperazin-1-yl) ethanol moieties, which were evaluated for antifungal activity against standards and clinically isolated yeasts, and their MIC structures were compared with those of fluconazole. Nitrotriazole derivatives 11a-d and compounds 12g and 11b containing two chlorine atoms exhibited good activity against the tested fungus, notably some fluconazole-resistant species. Compounds 11a, 11b, and 12g with 2,4-difluorophenyl or 2,4-dichlorophenyl groups had more excellent antifungal activity (Figure 13).

In vitro antifungal activities of new triazole derivatives of ravuconazole and isavuconazole were demonstrated against eight fungal isolates. Compounds 13e (2-F), 13f (2, 3-diF), and 13g (2, 4-diF) in particular displayed activity to ravuconazole, demonstrating that the 2,4-diflourophenyl group is more active than the 2,5-diflourophenyl group. Compounds without a fluoro substitution on the phenyl ring, such as 13a (4-CH₃), 13c (4-SO₂-CH₃), 13b (4-NO₂), and 13d (4-CN), were less active than those with fluorophenyl groups, such as 13k (2, 6-diF),13h (2, 5-diF), and 13l (2, 4, 6-triF) (Figure 14) [97].

Chen et al. [98] investigated a class of novel antifungal triazoles, and compound 14l () showed greater antifungal activity versus Candida glabrata and Candida albicans. Furthermore, compounds 14j, 14k, 14l, 15a, and 15b (–0.5 μg/mL) were shown to be more effective than fluconazole () against C. glabrata. SARs revealed that 3-substitutions (14d, 14e, and 14f) were more favorable than the 4-substitutions (14b, 14c), while electron-rich thiophene (14h, 14i) significantly outperformed the electron-deficient pridinyl group in antifungal activity (14g). Antifungal activity may be enhanced by replacement of the phenyl group of compound 14a by a cycloalkyl group, namely, cyclopentyl (14j), cyclohexyl (14k), and cyclopropyl (7l). In contrast, tert-butyl substitution (14m) only showed modest activity (Figure 15).

Compared to fluconazole and 5-flucytosine, the new fungicidal hybrids of 5-flucytosine and fluconazole showed modest antifungal activity. Surprisingly, a hybrid of 3,4-dichlorobenzene can inhibit clinical-resistant strain C. albicans and the growth of C. albicans ATCC 90023 with MIC values of 0.02 and 0.008 mM, respectively. Compound 16e inhibited C. albicans rapidly, whereas compound 16a lacked fungicidal activity due to the lack of substituents on the phenyl ring (ure 16) [99].

Xu et al. [100] described a series of novel triazole derivatives having γ-lactam that were screened for antifungal activity against six pathogenic fungi in vitro. Furthermore, the pyridyl- and phenyl-substituted compounds 17d and 17e showed moderate antimicrobial activity against Cryptococcus neoformans and Candida spp. (Figure 17).

Zhang et al. [101] reported the triazole sequence as a miconazole analogue with antifungal against five fungi. Among these compounds, 18b, 3,4-dichlorobenzyl had the highest activity. Furthermore, the antifungal activity of 3,4-dichlorobenzyl compound 18b (), 2,4-difluorobenzyl derivative 18c (MIC = 4 μg/mL), and 2-fluorobenzyl miconazole analogue 18e (MIC = 16 μg/mL) due to F or Cl may be significantly improved over nitro group compound 18d (nitrobenzyl). Surprisingly, substituted benzyl triazoles (–16 μg/mL) showed more potency than monosubstituted benzyl compounds (–32 μg/mL) (Figure 18).

The antifungal activity of a novel triazole-piperdine-oxadiazoleside group against clinically important fungal pathogens was investigated. Particularly, 19g () and 20b () showed high activity versus Candida albicans including fluconazole-resistant strains. Compounds 19c, 19d, 19h, 19n, and 20a had greater activity () than fluconazole (). Additionally, the presence of pridinyl group (19a and 19l) 1,2,4-oxadiazole derivatives reduces antifungal activity. On the contrary, compound 19n with furan demonstrated better activity than compound 19b with substitutions on the phenyl ring that revealed distinct effects on antifungal activity. Furthermore, 4-methoxyl (19f), 4-fluoro (19h), and 4-trifluoromethyl (19g) alterations demonstrated promising antifungal activity, with 19g showing the most activity against C. albicans (). Surprisingly, compound 19c exhibited significant fungicidal activity. In contrast, the antifungal activities of 4-ethyl (19k), 4-chloro (19j), and 4-nitro (19o) derivatives were decreased. On the other hand, fluorine-containing 1,2,4-oxadiazole derivatives such as 20f, 20i, and 20j demonstrated modest antifungal activity. Finally, the heterocyclic pyridinyl derivative 20a demonstrated the greatest activity (Figure 19) [102].

Mahmoudi et al. [103] evaluated some 1,2,4-triazole alcohols bearing N-(halobenzyl) piperazine carbodithioate scaffold as effective antifungal agent in vitro bioassays versus C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis in which the best activity indicated N-(4-chlorobenzyl) derivative 21b with MIC values of 0.063–0.5 mg/mL, being several times more effective than fluconazole. Furthermore, the 3-chlorobenzyl compound 21a displayed a good activity toward both albicans and non-albicans species of Candida. Generally, according to MICs, 2, 4-difluorophenyl derivatives were more active than their dichlorophenyl compounds. In addition, SAR studies revealed that 2,4-difluorophenyl-carbinol was higher than the 2, 4-dichlorophenyl-carbinol scaffold. Moreover, assessment against fluconazole-resistant isolates showed that compound 21b was active against C. albicans, C. krusei, and C. parapsilosis isolates, with MIC values of 2 to 16 mg/mL (Figure 20).

Ciprofloxacin and itraconazole were employed to screen 1,2,4-triazole derivatives fused with novel benzene-ethanol which were assessed at concentrations ranging from 0.125 to 64 mg/mL. Furthermore, compounds 22a, 22g, and 22i showed much better growth inhibitory activity on C. albicans with MIC of 32 mg/mL (itraconazole was introduced as the standard drug MIC 1 mg/mL). Electronegativity, like substituent groups on the para and ortho positions of a benzene ring, can be effective in antifungal activity (Figure 21) [104].

A class of 1,2,4-triazole derivatives has been tested toward Magnaporthe oryzae. Aromatic ring structures revealed that the methyl group at position 1,4 of the phenyl ring 23b and the phenyl moiety at the para position of phenyl 23c reduced antifungal activity. When an electron-withdrawing fluorine atom entered this position (23e), the antifungal activity increased slightly. An electron-withdrawing group (trifluoromethyl group) had a positive efficacy on increasing the antifungal activity of this synthetic series (comparison of antifungal activity 23b with 23f). The introduction of two chlorine atoms to the phenyl moiety had a distinct effect on increasing antifungal activity. Compound 23g with the 2,4-dichlorophenyl analogue slightly increased the antifungal activity, while compound 23h with the 3,4-dichlorophenyl analogue notably reduced the antifungal activity. The mono chlorine substitution at position 4 of the phenyl ring (23i) reduced the antifungal activity of these synthesized derivatives. According to the preceding considerations, 23e demonstrated remarkable fungicidal activity in this synthetic series. The effect of the chlorine atom on the various positions of the phenoxy moiety (ring B) such as 24a, 24b, and 24c can lead to an increase in antifungal activity. As a result, the fungicidal activity of the analogue without a chlorine substituent at ring B (24j) was the most effective against M. oryzae among these compounds (Figure 22) [105].

4.2. 1, 2, 4-Triazole Hybrids

Al-Wabli et al. [106] estimated the antifungal characteristics of a variety of novel indole-triazole compounds. The MIC value of compound 25f, which included N-phenyl and 3,4-dichlorobenzyl moieties, was 2 mg/mL against Candida albicans. In addition, the para benzyl substituent exhibits antifungal activity. Also, MIC values for compounds 25b, 25c, 25d, 25e, 25f, and 25g having a phenyl moiety on the triazole ring are 250–500 μg/mL against Bacillus subtilis. Meanwhile, compounds 25o, 25p, and 25q with an N-cyclohexyl substituent showed moderate to good activity toward the tested Candida albicans strain (Figure 23).

The nortopsentin analogues containing 1,2,4-triazole demonstrated good antifungal activity. Compounds 26a, 26d, and 26f were more fungicidal toward Cercospora arachidicola Hori than chlorothalonil and carbendazim (commercial fungicides). Compounds 26d and 26f indicated better actions against most of the fourteen plant pathogens (Figure 24) [107].

According to the study by Ahuja et al. [108], compound 27c has a lower ED50 value than the triazole fungicide propiconazole. Significantly, compound 27c showed the highest activity compared with other experimental fungi, with an ED50 value of 16 to 21 μg/mL, which is higher than the ED50 values of the standard commercial fungicides used (tilt: 20–25 μg/mL and carbendazim: 150–230 μg/mL (Figure 25).

Microbiological studies revealed that benzimidazole-1,2,4-triazole hybrid compounds 28m, 28n, 28f, and 28g had good fungicidal activity (MIC50 values of 0.78 to1.56 μg/mL) because of the presence of a fluoro or chloro substituent at the C-para position of phenyl, whereas compounds 28c, 28a, and 28b did not. Compounds 28d and 28e demonstrated adequate fungicidal activity (MIC50 –3.12 μg/mL). Compound 28l exhibited comparable antifungal activity with reference drugs fluconazole and ketoconazole. As a result, chloro or fluoro substitution at the C-5 position of benzimidazole is vital and could have had a significant influence on antifungal activity (Figure 26) [109].

The benzimidazole-triazole compounds showed moderate antifungal activity toward Candida krusei (ATCC 6258), Candida glabrata (ATCC 90030), Candida albicans (ATCC 24433), and Candida parapsilosis (ATCC 22019), with MIC50 values ranging from 12.5 to 0.78 mg/mL. The findings revealed that compound 3,4-dihydroxy has an influence on the activity (Figure 27) [110].

Novel tri-substituted 1,2,4-triazoles containing benzimidazole were tested for antifungal efficacy against three plant pathogenic fungus, and compounds 30e and 30g showed potent activity against Venturia nashicola. However, 30d and 30f indicated sufficient activity against Fusarium graminearum (Figure 28) [111].

Luo et al. [112] reported a new group of benzimidazole-derived triazoliums and naphthalimide triazoles that have been thoroughly tested for antifungal activities. Triazoliums 31g and 31f with 3-fluorobenzyl and 2-chlorobenzyl moiety demonstrated the highest antifungal activity (–19 mg/mL) against all tested fungal strains. However, 2,4-di-chlorobenzene triazolium 31h (–29 mg/mL) showed more efficacy than fluconazole (–230 mg/mL). Furthermore, bis (4-fluorobenzyl) triazolium 31b (–19 mg/mL) displayed high activity against all of the microorganisms tested except S. cerevisiae (Figure 29).

The antifungal efficacy of 1,2,4-triazoles having quinoline moiety against A. fumigatus and Candida albicans was highest owing to methoxy and chloro substituents. As a result, 32e, 32g, and 32m derivatives with methoxy and chloro substituents had the highest enhanced activity (Figure 30) [113].

D’Souza et al. [114] investigated the fungicidal of new quinoline-triazoles. Compounds 33b and 34b with chlorine substituents on the aromatic ring demonstrated more antifungal activity than (33e, 33f, 34e, and 34f) that included OCH₃ and CH₃ (Figure 31).

Fan et al. [115] investigated the antifungal activity of 1,2,4-triazolo [4,3-a]pyridine-containing quinazoline thioether derivatives at 50 mg/mL. Except for compound 35c against the fungi Verticillium dahlias and Fusarium oxysporum (inhibition rates of 65.4 and 52.5%, respectively), all of these compounds failed to demonstrate apparent fungicidal activity (≥45%) against the case fungi, with compound 35h against the pathogen V. dahliae (46.8%) (Figure 32).

Fan et al. [116] investigated the antifungal activity of quinazolin-containing 1,2,4-triazoles against six significant phytopathogenic fungi in agriculture. Furthermore, compounds 36h and 36g were showed a remarkable fungicidal activity toward Gloeosporium fructigenum at 50 mg/mL, comparable to the commercial antifungal hymexazol (Figure 33).

Most of the 2-phenoxy-benzo [g] [1, 2, 4] triazolo [1,5-a] quinazoline derivatives indicated in vitro antifungal activity against ten fungal strains except C. neoformans. Nevertheless, 37a and 37b exhibited activity only against A. niger and A. fumigatus. Compounds 37c, 37d, 37e, 37f, and 38b revealed excellent fungicidal activities against A. fumigatus (–1.95 μg/mL), and 37g showed the ability to produce amphotericin B (/mL). In contrast, 38b had stronger inhibition with respect to the reference drug toward S. racemosum () and 37e confirmed similar activities to amphotericin B (). In addition, compounds 37c-37e, 38a, and 38b showed the highest activity versus G. candidum (–0.98 μg/mL) as compared with amphotericin B () (Figure 34) [117].

El-Attar et al. [118] investigated the antifungal activities of 1,2,4-triazolos [4,3-a]-quinoxaline derivatives with various substituted pyrazole moieties at position 4. When compared with the reference clotrimazole (), compound 39 demonstrated reasonable growth inhibition () against C. Albicans. Compounds 39, 41a, and 41b inhibited only weakly () growth against the same organism. Clotrimazole activity against the fungus A. fumigatus was reduced by one-quarter in studies 39 and 42. Regarding the activity against R. oryzae, compounds 39, 40, 41a-c, and 42 showed weak growth inhibition () when compared with the reference clotrimazole () (Figure 35).

Yang and Bao [119] demonstrated that 1,2,4-triazole derivatives (43a-43k) containing N-(substituted phenyl) acetamide and the quinazolinylpiperidinyl moiety group did not exhibit remarkable inhibition activity against phytopathogenic fungi such as Phytophthora infestans, Verticillium dahliae, and Gibberella zeae) at 50 mg/mL save compounds 43e and 43k that showed modest inhibitory activity against the fungus G. zeae (Figure 36).

Sompalle et al. [120] investigated the antifungal activity of a class of 1,2,4-triazole-quinazolinethiones (44a-l) against Aspergillus niger (A. niger) and Aspergillus flavus (A. flavus) in combination with the commonly used antifungal drug fluconazole (Figure 37).

All triazole derivatives with N-alkylated groups were tested for fungicidal activity toward Candida albicans and Aspergillus flavus and anthelmintic activity against Pheretima posthuma, and the compound containing group CH₃ at the ortho position of the phenyl ring showed good inhibition with the inhibition zone and against A flavus and C albicans in comparison with a standard antifungal drug, Nystatin, while the antifungal activity of the other structures was lower (Figure 38) [121].

Jin et al. [122] investigated the fungicidal activity of novel compounds containing 1,2,4-triazole with different substituted groups toward Gibberlla nicotiancola, Pythium solani, Gibberlla saubinetii, and Fusarium oxysporum f.sp. niveum in vitro. Compound 46 had good activity against the case fungus, indicating that 1,2,4-triazole-imidazole can contribute to antifungal properties. Methyl at position Q increased the activity, the activity order is 47>46, and compound 47 demonstrated a remarkable antifungal activity. As a result, positions P and Q may have an impact on the activity at the same time (Figure 39).

1,2,4-Triazole derivatives with a pyrimidine moiety were evaluated for fungicidal activity, with compounds 50c and 50d showing the best antifungal activity against Phompsis sp. that was even better than pyrimethanil (32.1 mg/mL). Compound 50d, on the other hand, had higher activity against B. cinerea and B. dothidea with 55.1 and 40.1 mg/mL, respectively, when compared with Pyrimethanil (57.6 and 62.8 mg/mL) (Figure 40) [123].

Antifungal evaluation [1, 2, 4] of triazolo [5,1-b] quinazolin-8(4H) one scaffolds (51a-n) in vitro exhibited that compounds 51e and 51i display higher activity than standard drug griseofulvin (MIC 500 mg/mL) against C. albicans. Surprisingly, the substitution at the C-6 carbon of the final moiety and para-substituted phenyl ring was responsible for variable biological results, while the triazole with nonsubstituted or diversely para-substituted (Cl, OCH₃, and NO₂) phenyl core or heterocyclic nucleus showed the best properties. In addition, the compounds having OCH₃ group substitution (compound 51f) effectively showed poor inhibition toward A. clavatus and A. niger inhibited the S. aeruginosa, P. aeruginosa, and S. pneumonia strains, although the derivative with the electron-withdrawing group such as NO₂ (compound 51i) efficiently inhibited the E. coli bacterial strain as well as was found potent toward the C. albicans strain. Finally, compound bearing heteroaryl substitution (compound 51l) led to the improvement in the activity against the E. coli strain (Figure 41) [124].

All 1,2,4-triazole having amine derivatives were evaluated and shown to be effective in inhibiting fungal pathogens with MIC values ranging from 1 to 256 μg/mL. They were proposed as the potential antifungal agents that synthesized under optimized conditions as 3(5)-substituted 1,2,4-triazol-5(3)-amine 52. As starting materials, however, several heteroaryl hydrazides and aryls were used as starting materials (Figure 42) [125].

Appna et al. [126] described the fungicidal activity of novel 1,2,4-triazole fused pyrido [2,3-d] pyrimidine derivatives (53a-d and 54a-c) against different Candida strains. The antifungal activities of the synthesized compounds 53d, 54b, and 54c were shown. SAR investigations revealed that trifluoromethyl, fluoro, bromo, and nitro groups on the furyl and phenyl rings of pyrido [2,3-d] pyrimidine could increase antifungal activity. Compounds (53d, 54b, and 54c) 4-fluoro-2-chlorophenyl triazole and 2-furyl substituent in pyrido [2,3-d] pyrimidine exhibited the best activity. As well, 4-nitrophenyl triazole in combination with 2-furyl pyrido [2,3-d] pyrimidine (54b) exhibited the same activity. The antifungal effects of 2-chloro-4-fluoro phenyl triazole with 2-phenyl pyrido [2,3-d] pyrimidine (53d) were favorable (Figure 43).

A new series of 1,2,4-triazole derivatives were synthesized by Singh et al. The antifungal characteristics of the compounds showed that most of them could effectively inhibit the growth of the tested fungal strains. However, none of them were superior to the reference drug fluconazole. Compound 55l had the most potent antifungal activity against both fungi. 55l revealed comparable activity (A. niger: ; C. albicans: ) with the reference fluconazole (A. niger: ; Candida albicans: ). Apart from that, antifungals 55f (A. niger: ; C. albicans: ) and 55a (A. niger: ; C. albicans: ) were found to be potent (Figure 44) [127].

Jin et al. [128] investigated the antifungal effects of a variety of 4-amino-5-substituent-1,2,4-triazole-3-thione Schiff bases toward Pythium solani, Gibberlla nicotiancola, Gibberlla saubinetii, and Fusarium oxysporum f.sp. niveum. Compounds 56a and 56b showed considerable activity against the majority of the test fungi, while derivative 56a was more potent toward Gibberlla saubinetii and Gibberlla nicotiancola than triadimefon. The antifungal activity of 56a-d and 57a-d analogues was tested against four plant pathogenic fungi, including Pythium solani, Fusarium oxysporium f.sp. niveum, Gibberlla nicotiancola, and Gibberlla saubinetii (Figure 45).

Zhang et al. [129] displayed a new class of piperazine-containing 3-(furan-2-yl)-1,2,4-triazole important in vitro fungicidal activity toward a variety of plant fungi. In particular, compounds 58a, 58b, 58c, 58d, 58e, 58f, 58g, and 58h showed triadimefon against a variety of test fungi. Compounds 58g, 58f, and 58h having performed better than others ( or Cl). In comparison, the SARs of the compounds revealed 2-positions of the para position of substituted benzylideneamino and ortho position of phenylpiperazine, where a large group would be favorable for higher fungicidal activity. Finally, compounds with an EWG at the benzyl ring position or an electron-donating group at the 2,4-position of the benzene ring, such as 58b and 58a, demonstrated higher activity (Figure 46).

Trialkylamine compounds having a triazole moiety were evaluated in vitro for antifungal activity against six phytopathogenic fungi at 50 mg/mL (Magnaporthe grisea, Curvularia lunata, Alternaria solani, Fusarium solani, A. alternata, and F. graminearum). Compounds 59k (3-F), 59m (3,4-diCl), and 59n (4-Br) had good activity toward A. solani with EC50 values of 2.88, 8.20, and 1.92 mg/mL, respectively. Furthermore, compounds 59c (4-Cl), 59f (3,4-diCl), and 59d (2-Br) showed good antifungal activity against F. graminearum with EC50 values of 11.60, 5.14, and 16.24 mg/mL, respectively. Also, electron-donating groups 59o (Me) or 59p (OMe) considerably reduced the activity. In contrast, the presence of halogen atoms such as 59k (3-F), 59c (4-Cl), (3,4-diCl), and 59n (4-Br) might increase the activity (Figure 47) [130].

1,2,4-Triazole-pyridine products with hydrazone scaffold (compounds 60a-60h) were tested in vivo at 100 mg/mL against Stemphylium lycopersici (Enjoji) Yamamoto (SL) and Fusarium oxysporum sp. Cucumebrium (FO). Compound 60d as well as compounds having electron-donating groups at the 4-position of benzene such as 60e (p-N (CH₃)₂), 60b (p-F), 60f (p- CF₃), and 60g (p-CH₃) demonstrated strong antifungal activities. As a result, the furan ring-substitution exhibited more activity against SL and FO than the aryl or alkyl groups. Furthermore, both poly- and single-substituted benzene compounds showed excellent activity against FO (Figure 48) [131].

Remarkable antifungal activity of a number of new 1,2,4-triazole derivatives against different strains of Aspergillus fumigatus, Candida albicans, and Candida crocus has been reported in comparison with those of commercial fungicides ketoconazole and itraconazole. All of the derivatives investigated, the dichloro urea analogue and bromo substituted triazole, stand out as the most favorable compounds. The most potent compounds against A. fumigatus were 64l, 61b, 61a, and 61c, with MIC values ranging from 0.114 to 0.230 μmol/mL. Instead, amide analogues such as 62f can influence the activity, with the amide moiety 62f having higher activity than less bulky triazoles such as 65o and 65p. Furthermore, compound 63h with the sulfonamide substitution is responsible for the activity reduction. Compounds 64l and 61b have the highest activity, being several times more potent than ketoconazole. Conversely, these derivatives were less active than itraconazole (Figure 49) [132].

Dincel et al. [133] screened a group of novel hydrazinecarbothioamide (66), 4-thiazolidinone (67), and 1,2,4-triazole-3-thione (68) for the fungicidal properties against C. parapsilosis ATCC 22019, C. Albicans ATCC 10231, M. gypseum NCPF580, C. krusei ATCC 6258, T. tonsurans NCPF245, and T. mentagrophytes var. echinacea. Generally, 1,2,4-triazole-3-thiones and 4-thiazolidinones showed better fungicidal activity rather than thiosemicarbazide derivatives. As a result, the 3-allyl substitution of 4-thiazolidinones is critical for their antifungal activity. Compounds 67d (-), 68c (), and 68d () had the highest fungicidal activity against S. aureus (). Also, 68c () and 68d () showed the greatest activity against E. coli (). In addition, 68d () showed the greatest activity towards P. aeruginosa () (Figure 50).

Cheng et al. [134] investigated the fungicidal activity of new groups of 1,2,4-triazole benzoyl aryl amines. The findings revealed a clear relationship between the structure and training in these compounds as well. The electron-withdrawing group oi-pr(isopropyl) at the para position has a favorable impact on high activity, and the preferred groups were alkoxy carbonyls. This compound indicated the most effective fungicidal activities with EC50 values of 0.12, 0.19, and 0.01 mg/mL against S. sclerotiorum, F. graminearum, and G. graminis var. tritici, respectively. Alkoxy carbonyl of these ester carbonyls revealed the highest activities (69a-b and 69c-g). In contrast, no significant increase in the activity was observed when more than one electron-withdrawing group was added to aniline. For instance, if the second electron-withdrawing groups such as CF₃ or Cl were added to the meta situation of aniline, the activity against G. graminis var. tritici would be reduced (69e and 69f) (Figure 51).

The evaluation indicated that all 1,2,4-triazole derivatives had fungicidal activity, with MIC values ranging from 0.02 to 0.52 mM, which was better than bifonazole (MIC values of 0.32–0.64 mM) and ketoconazole (MIC values of 0.28–1.88 mM). Compound 70c, having a MIC value of 0.02–0.04 mM, exhibited the best antifungal activity rather than compound 70a (Figure 52) [135].

Wu et al. [136] evaluated the fungicidal activity of a novel series of 1,2,4-triazole derivatives containing an amide moiety. Compounds 71a, 71d, 71e, and 71f had the highest antifungal activity against Botrytis cinerea. Meanwhile, compound 71b, when R was CH₃, exhibited better antifungal property against Phomopsis sp., compared with that of pyrimethanil. SAR studies revealed that 4-pyridine in the R substituent group and the smaller alkyl substituent groups (H or CH₃) could have a favorable influence on the activity, such as 71a>71b>71c. Meanwhile, when is added to the 4-positions of phenyl and substituted phenyl, the action against Phomopsis sp., B. dothidea, and B. cinerea rises in the sequence 71d>71g>71k. Furthermore, when -pyridine, the antifungal activities of the corresponding compound 71h against Phomopsis sp., B. dothidea, and B. cinerea were higher than those of compound 71e (-pyridine) (Figure 53).

Yurttaş and CantŘrk [137] investigated triazole-oxadiazole compounds against C. krusei, C. glabrata, C. albicans, and C. parapsilosis and found that triazole-oxadiazole derivatives 72e and, particularly, 73i had the highest activity against C. glabrata and C. albicans (). The oxadiazole rings of these derivatives differ due to the benzothiazole and phenyl rings linked to the acetamide molecule. Meanwhile, compounds 72e () and compound 73e () were found to have the highest activity (Figure 54).

Li et al. [138] reported a group of N-phenylacetamide containing 1,2,4-triazole derivatives (74a-f) that were screened in vitro for antifungal assessment, and specific compounds, such as 74b-f derivatives, inhibited the growth of the tested fungus. Among all synthesized compounds, 74a exhibited no antifungal activity. Moreover, mono-substituted halogen substituents in the benzene ring, in either the ortho or the para position, displayed antifungal activity (Figure 55).

The antifungal properties of the synthesized 1,2,4-triazole-3-yl-mercapto derivatives toward two Candida albicans strains (C. albicans ATCC 10231 and C. albicans ATCC 18804) and one non-Candida albicans strain (C. krusei ATCC 6258) were evaluated. Its antifungal activity was shown by the presence of a halogenated aryl substituent linked to the 3-mercapto group. Compounds 75d, 75f, and 75g had smaller MIC values than the other 1,2,4-triazolyl-thioethers, indicating that the 1,2,4-triazole-3-yl-mercapto derivatives with a 4-Cl-phenyl component had more excellent antifungal activity against the Candida krusei ATCC 6258 strain. In this series, compound 75d in this series has the lowest MIC value (Figure 56) [139].

Antifungal activities of new myrtenal derivatives containing 1,2,4-triazole were tested against Physalospora piricola, Fusarium oxysporum f.sp. cucumerinum, Cercospora arachidicola, Alternaria solani, and Gibberella zeae at 50 mg/mL. Among these compounds, 76a (), 76c (), and 76e ( Bn) had the most significant antifungal activity against P. piricola. Among these derivatives, 76a () 76c (), and 76e ( Bn) indicated the highest antifungal activity against P. piricola (Figure 57) [140].

Cheng et al. [141] evaluated a series of 4,5-disubstituted-3-S-(β-D-acetyl glycosyl)-1,2,4-triazoles for their antifungal activities in which compounds revealed reasonable activities at the concentration of 50 μg/mL. Particularly, compounds 77c, 77g, 77n, and 77p displayed 60–68.6% inhibitory rates against B. cinerea and 77c, 77d, 77g, 77m, 77n, and 77p derivatives exhibited 63.6%–78.8% inhibitory rates against S. sclerotiorum, with the antifungal activity of being lower than those of the other compounds against S. sclerotiorum. In other words, compounds containing a galactosyl moiety, such as compound 77n, demonstrated highly favorable antifungal action, whereas compounds with a glucosyl moiety showed comparably weak antifungal activity (Figure 58).

Bitla et al. [142] synthesized and screened bis(1,2,3 and 1,2,4)-triazole derivatives for antifungal activity, and compounds 78a, 78d, 78f, and 78i had the highest activity. It is remarked that bromo and chloro substitutes at meta and para positions of the aryl ring were highly important. Compound 78f indicated superior activity against S. aureus MTCC 96 () (Figure 59).

Beyzaei et al. [143] synthesized and tested a new class of 1,2,4-triazole-3-thiones in glycerol/potassium carbonate and assessed them for antifungal activity. Significant inhibitory special effects were detected notably against fungal infections. Fusarium oxysporum and Aspergillus fumigatus were inhibited with all of them. The most excellent antifungal activities indicated triazole 79c that contains -nitrophenyl has the highest antifungal activity as well as the high-affinity binding to the receptor. Hydrogen bonds between the N-1 azole ring and some amino acid residues in the target enzyme interact predominantly. These findings might aid in the development of antifungal drugs (Figure 60).

Some studies have been conducted on the fungicidal activities of the novel 1,2,4-triazole derivatives. Compounds 80a-d (Figure 61) in particular showed high antifungal activity. The relationship between biological activity and structure revealed that compounds with the sulfur atom exclusively in the thiol form exhibited activity. Furthermore, compounds 80a and 80c, at a concentration of 1000 mm, inhibit the growth of C. albicans by 35–40%, respectively [144].

Sidhu and Kukreja [145] reported new compounds based on lead hybridization of 1,2,4-triazoles with fluorinated benzothiazol-2-yl that were tested for fungicidal activity against P. striiformis, D. oryzae, and U. hordei in contrast with conventional fungicides. Furthermore, derivatives 81b and 81c are active against most of the experimental fungi. Compounds 81a and 81e caused the antifungal potential of EC50 0.23 and 0.19 mmoles/L, respectively, against P. striiformis that was compared to the standard fungicide (EC50 value 0.10 of mmoles/L). Compound 81a has the greatest EC50 value (0.17 mmoles/L) against U. hordei when compared to Vitavax (EC50 value of 0.09 mmoles/L) (Figure 62).

Shingare et al. [146] presented a new series of pyrazole bearing triazolo-thiadiazole derivatives (82a-l) which were evaluated to have antifungal activity versus A. Niger, C. albicans, and A. clavatus along with nystatin and griseofulvin as standard drugs. Amongst them, compounds 82b and 82j revealed good antifungal activity. Compound 82j has shown the most activity (Figure 63).

The antifungal activity of 1,2,4-triazolo containing thiadiazoles (83a-e) and 1,2,4-triazol-3-ylthio-N-4-aryl) acetamides (84a-d) was evaluated. Compound 84a had good activity toward A. flavus with a MIC value of 70 μg/mL compared with standard fluconazole; derivatives 83d, 83a, 84c, and 84a demonstrated moderate activity (Figure 64) [147].

Bai et al. [148] assessed several novel 1,2,4-triazole analogues for antifungal activity against eight phytopathogens and found that the majority of them exhibited acceptable to outstanding fungicidal characteristics. Almost all of the compounds demonstrated moderate to excellent fungicidal activity toward the tested phytopathogens. In general, the fungicidal activity of methyl oxime ether group 85 () was significantly greater than benzyl oxime ether group 86 (). It is clear that electron-drawing groups at the 2-position of the phenyl ring, such as 85b, 85d, 86b were more helpful for fungicidal activity. Because of the halogen substituent effect, compounds 85b, 85d, 85g, 85k, and 86b demonstrated significantly higher inhibitory activities against fungal pathogens than other compounds, with the chlorine atom playing a more significant role in improving fungicidal activity in each position of the benzene ring.

Furthermore, the prevention rates of compounds 85d, 86e, and 85f against all of the fungi examined were meager. It is shown that for benzyl oxime ether series 85, a bulky 2-tert-butyl group on the benzene substituent was not best for the activity. Compound 85d (2-Cl-4-Br) containing two mixed halogen atoms showed broad-spectrum fungicidal activity, with EC50 values of 1.59, 0.46, 0.27, and 11.39 mg/L against four fungal pathogens (Figure 65).

5. Conclusion

A privileged structure in medicinal and organic chemistry is 1,2,4-triazole-hybrids having a broad spectrum of antifungal activity. The 1,2,4-triazole nucleus and its derivatives are essential scaffolds in the discovery and development of drugs that have a multitude of biological activities. An acceptable reason for its broad biological profile is a small and stable cyclic ring structure wherein the nitrogen atoms can act both as hydrogen bond donor and as acceptors at the active site of the receptor. The pentacyclic triazole ring processes plasticity for the synthesis of a number of derivatives due to of its multifold binding sites. This potent scaffold will act as a lead molecule in drug synthesis in the future. The various methods for the regioselective synthesis of 1,2,4-triazole-scaffold will be a great tool in medicinal chemistry in the future. The most challenging problem in fungal therapy is antifungal resistance, which may be progressed by drug target overexpression. This review is focused to summarizing recent research on 1,2,4-triazole-hybrids as fungicidal agents over the last decade. It will aid researchers and medicinal chemists in the discovery and the synthesis of new antifungal compounds with 1,2,4-triazole-moiety.

Abbreviations

A. flavus:	Aspergillus flavus
A. niger:	Aspergillus niger
C. albicans:	Candida albicans
C₂H₃N₃:	Molecular formula of 1,2,4-triazole derivatives
CuO:	Copper (II) oxide or cupric oxide
CYP51:	Lanosterol 14α-demethylase
ED50:	Effective dose for 50% of the population
EWG:	Electron withdrawing group
FLC:	Fluconazole
FO:	Fusarium oxysporum
K₃PO₄:	Tripotassium phosphate
MIC:	Minimum inhibitory concentration
NaOH:	Sodium hydroxide
SAR:	Structure-activity relationship
SL:	Stemphylium lycopersici.

Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. We have presented all data in the form of figures.

Ethical Approval

This research has been ethically approved (no. 99310) IR.FUMS.REC.1400.013.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

The conception, design, writing, and revision of the study were done by E. Z. The first draft of the manuscript was written by E. Z., Z. K., M. M., A. S., M. F., and A.K. Also, E. Z. and M. M. played the role of the first author in this manuscript; all authors approved the final manuscript.

Acknowledgments

The authors wish to thank the Noncommunicable Diseases Research Center, Fasa University of Medical Sciences.

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Copyright © 2022 Zahra Kazeminejad et al. 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.

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