Syntheses of Novel 4-Substituted N-(5-amino-1H-1,2,4-triazol-3-yl)pyridine-3-sulfonamide Derivatives with Potential Antifungal Activity

Abstract

Candidiasis represent a serious threat for patients with altered immune responses. Therefore, we have undertaken the synthesis of compounds comprising a pyridine-3-sulfonamide scaffold and known antifungally active 1,2,4-triazole substituents. Thus a series of novel 4-substituted <i>N</i>-(5-amino-1<i>H</i>-1,2,4-triazol-3-yl)pyridine-3-sulfonamides have been synthesized by multistep reactions starting from 4-chloropyridine-3-sulfonamide via <i>N</i>'-cyano-<i>N</i>-[(4-substitutedpyridin-3-yl)sulfonyl]carbamimidothioates which were further converted with hydrazine hydrate to the corresponding 1,2,4-triazole derivatives <b>26</b>-<b>36</b>. The final compounds were evaluated for antifungal activity against strains of the genera <i>Candida</i>, <i>Geotrichum</i>, <i>Rhodotorula</i>, and <i>Saccharomycess</i> isolated from patients with mycosis. Many of them show greater efficacy than fluconazole, mostly towards <i>Candida albicans</i> and <i>Rhodotorula mucilaginosa</i> species, with MIC values ≤ 25 µg/mL. A docking study of the most active compounds 26, 34 and 35 was performed showing the potential mode of binding to <i>Candida albicans</i> lanosterol 14α-demethylase. Also in vitro cytotoxicity of selected compounds have been evaluated on the NCI-60 cell line panel.