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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 398 - 403
• Main Authors: Pagniez, Fabrice, Lebouvier, Nicolas, Na, Young Min, Ourliac-Garnier, Isabelle, Picot, Carine, Le Borgne, Marc, Le Pape, Patrice
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Informa Healthcare; Taylor & Francis Group
• Subjects: Animals; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biochemistry & Molecular Biology; Biosynthesis; Candida - drug effects; Candida - enzymology; Candida - metabolism; Candida species; Cell Line; Chemical Sciences; Chemistry, Medicinal; Cytotoxicity; Ergosterol; Ergosterol - antagonists & inhibitors; Ergosterol - biosynthesis; ergosterol production; Female; Fluconazole; Humans; Indoles; Indoles - chemistry; Indoles - pharmacology; in vivo evaluation; Isopropyl alcohol; Life Sciences; Life Sciences & Biomedicine; Medicinal Chemistry; Mice; Microbial Sensitivity Tests; Microbiology and Parasitology; Mycology; Pharmaceutical sciences; Pharmacology; Pharmacology & Pharmacy; Phospholipase A2; phospholipase A2-like activity; Research Paper; Science & Technology; Species Specificity; Sterols; Triazole-indole hybrid; Triazoles - chemistry; Triazoles - pharmacology; Virulence factors; Voriconazole; ergosterol production; LOCALIZATION; phospholipase A2-like activity; in vivo evaluation; METABOLISM; Triazole-indole hybrid; CANDIDIASIS; PHOSPHOLIPASE-ACTIVITY; Candida species; ANTILEISHMANIAL ACTIVITY; in vivo evaluation
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2019.1705292

(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 (MIC 90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC 90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC 90 = 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.