Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent

Abstract

(2-(2,4-Dichlorophenyl)-3-(1<i>H</i>-indol-1-yl)-1-(1,2,4-1<i>H</i>-triazol-1-yl)propan-2-ol (<b>8 g</b>), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against <i>Candida,</i> particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on <i>C. glabrata</i> (MIC₉₀ = 0.25, 64 and 1 µg/mL, respectively), <i>C. krusei</i> (MIC₉₀ = 0.125, 64 and 0.125 µg/mL, respectively) and <i>C. albicans</i> (MIC₉₀ = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of <b>8 g</b> were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. <b>8 g</b> demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that <b>8 g</b> is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.