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In order to find new azole antifungals, we have recently designed a series of triazole alcohols in which one of the 1,2,4-triazol-1-yl group in fluconazole structure has been replaced with 4-amino-5-aryl-3-mercapto-1,2,4-triazole motif. In this paper, we focused on the structural refinement of the primary lead, by removing the amino group from the structure to achieve 5-aryl-3-mercapto-1,2,4-triazole derivatives 10a-i and 11a-i. The in vitro antifungal susceptibility testing of title compounds demonstrated that most compounds had potent inhibitory activity against Candida species. Among them, 5-(2,4-dichlorophenyl)triazole analogs 10h and 11h with MIC values of <0.01 to 0.5μg/mL were 4-256 times more potent than fluconazole against Candida species., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of new triazole alcohol antifungals were designed by replacing one of the triazolyl moiety from fluconazole with a distinct 4-amino-3-mercapto-1,2,4-triazole motif, which is found in some antimicrobial agents. The antimicrobial susceptibility testing of target compounds demonstrated that the direct analogs of fluconazole (difluorophenethyl-triazoles) were less active against fungi, while compound 10h containing dichloro substitutions on both phenyl rings of the molecule had potent activity against yeasts including Candida albicans (four strains) and Cryptococcus neoformans (MICs = 2-8 μg/mL). Also, compound 10h was active against Candida parapsilosis, Epidermophyton floccosum, and Trichophyton mentagrophytes, while it showed no activity against Gram-positive and Gram-negative bacteria. Finally, a molecular docking study suggested that compound 10h interacts suitably with lanosterol 14α-demethylase, which is the key enzyme in ergosterol biosynthesis.

A series of imidazolylchromanone oximes containing phenoxyethyl ether moiety, as found in omoconazole, were synthesized and evaluated against yeasts (Candida albicans and Cryptococcus gattii) and filamentous fungi (Aspergillus fumigatus and Exophiala dermatitidis). Although the title compounds showed marginal activity against filamentous fungi but all of them exhibited potent activity against C. gattii (MIC values ≤4 μg/mL). Among them, (3-chlorophenoxy)ethyl analog 7c with MIC value of 0.5 μg/mL was the most potent compound. Further molecular docking studies provided a better insight into the binding of designed compounds within the homology modeled active site of CnCYP51 (Cryptococcus CYP51-14α-demethylase)., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Previously, 2-alkylchromans have been introduced as non-azole inhibitors of 14α-demethylase. Accordingly, we incorporated imidazole ring on the 3-position of 2-alkylchromanones to design new inhibitors of 14α-demethylase and potential antifungal agents. Thus, a series of 2-alkyl-3-imidazolylchromanones were synthesized starting from 2-hydroxyphenacyl bromide. The trans-configuration of compounds was confirmed by NMR-spectroscopy. The antifungal activity of title compounds were evaluated against different fungi in comparison with fluconazole and miconazole. trans-2-(1-Pentyl)-3-imidazolylchroman-4-one (4d) showed the most potent activity against yeasts comparable to fluconazole. The experimental data based on (1)H NMR spectroscopy revealed that 2-alkyl side chain and 3-imidazolyl moiety in compound 4d exist predominantly in the di-equatorial conformation. While docking study with 14α-demethylase demonstrated that the di-axial form of compound 4d can be considered as active conformation.

A series of novel 3-(1,2,4-triazol-1-yl)flavanones were synthesized based on the N-phenethylazole pharmacophore of azole antifungals. The results of antifungal assay revealed that 4'-fluoroflavanone derivative 4c exhibited the best profile of activity against Candida and Saccharomyces strains. Compound 4c was 4-16 times more potent than reference drug fluconazole against Candida albicans and Saccharomyces cerevisiae. The molecular docking study with lanosterol 14α-demethylase, in silico toxicity risks and drug-likeness predictions were used to better define of title compounds as antifungal agents. The favorable drug-like property of compound 4c makes 3-(1,2,4-triazol-1-yl)flavanone prototype as a promising lead for the future development of azole antifungal agents., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)