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

Abstract

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC₉₀ = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC₉₀ = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC₉₀ = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g 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. 8 g 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 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.

Keywords:

• Triazole-indole hybrid
• Candida species
• ergosterol production
• phospholipase A2-like activity
• in vivo evaluation

Acknowledgements

A doctoral scholarship from the Research Association AGISMED to Mr Y-M. Na and Mr N. Lebouvier are gratefully acknowledged. We are also grateful to Mr. and Mrs. Le Floch (Yanikem s.a.r.l.) for their continued support.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This research was also financially supported by Yang Ji Chemical Company of South Korea.