Abstract
Owing to the growing need for antifungal agents, we synthesized a new series 2-((5-(4-(5-substituted-1H-benzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol-3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives, which were tested against Candida species. The synthesized compounds were characterized and elucidated by FT-IR, 1H-NMR, 13C-NMR and HR-MS spectroscopies. The synthesized compounds were screened in vitro anticandidal activity against Candida species by broth microdiluation methods. In vitro cytotoxic effects of the final compounds were determined by MTT assay. Microbiological studies revealed that compounds 5m, 5o, 5r, 5t, 5y, 5ab, and 5ad possess a good antifungal profile. Compounds 5w was the most active derivative and showed comparable antifungal activity to those of reference drugs ketoconazole and fluconazole. Cytotoxicity evaluation of compounds 5m, 5o, 5r, 5w, 5y, 5ab and 5ad showed that compounds 5w and 5ad were the least cytotoxic agents. Effects of these two compounds against ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of ergosterol level in C. albicans. Compounds 5w and 5d inhibited ergosterol biosynthesis concentration dependently. A fluorescence microscopy study was performed to visualize effect of compound 5w against C. albicans at cellular level. It was determined that compound 5w has a membrane damaging effect, which may be related with inhibition of biosynthesis of ergosterol.
Highlights
The Candida species are definitely the most important opportunistic fungal pathogens for individuals [1]
The synthesis of target compounds 5a–5ad was performed as outlined in Scheme 1
(0.78–1.56 μg/mL) against Candida strains. These findings show that the antifungal activity of the compounds 5w and 5ad is not due to general toxicity, but can be ascribed to their selective action against Candida species
Summary
The Candida species are definitely the most important opportunistic fungal pathogens for individuals [1]. For the therapeutic management of fungal infections, only four important classes of antifungal agents are available in clinical use. These are azoles such as fluconazole, itraconazole, and ketoconazole; polyene macrolides such as Amphotericin B and nystatin; 5-flucytosine; and echinocandins such as caspofungin and micafungin [10]. Several novel triazole antifungal drugs, such as voriconazole, posaconazole, ravuconazole and albaconazole, are available in the market or are at the late stages of clinical trials [14] These drugs act by competitive inhibition of the lanosterol 14α-demethylase (CYP51A1), which is the key enzyme in sterol biosynthesis of fungi. In this study, 30 new 2-((5-(4-(5-substituted-1Hbenzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol-3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives (5a–5ad) were synthesized and investigated for anticandidal activity
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