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 fluconazolesusceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC 90 ¼ 0.25, 64 and 1 mg/mL, respectively), C. krusei (MIC 90 ¼ 0.125, 64 and 0.125 mg/mL, respectively) and C. albicans (MIC 90 ¼ 0.5, 8 and 0.25 mg/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.

Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

“…CYP3A4, CYP2D6). Recently, we published extended biological exploration of 8g (in vitro and in vivo assays) and then we confirmed the full potential of this molecule [28]. Another major challenge is the emergence of resistance to azole antifungals among Candida species [58].…”

“…Comparison of this sub-series with the 1,2,4-triazole sub-series (unsubstituted indole derivatives 11a, 11b, and 11d) has shown that the triazole moiety decreased significantly the cytotoxicity (IC 50 > 100 µM), except for the 4-bromo derivative 11c (IC 50 = 38 µM), 8g, and its enantiomers. Indeed, the cytotoxicity values of 8g, (+)-(R)-8g, and (−)-(S)-8g (IC 50 = 35 µM [28], 32, and 30 µM, respectively) were two times higher than that of KTC and at least three times higher than those of FLC (IC 50 > 100 µM).…”

“…A toxicity index was determined as follow: IC 50 against MRC5/Geometric mean of the MICs against Candida spp. [28].…”

“… 1 IC 50 (half-maximal inhibitory concentration) values (µM) were expressed as the mean of triplicate measures. 2 Cytotoxicity activity of 8g previously determined [ 28 ]. …”

Synthesis of new piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction

“…For example, compound 1d could offer a new treatment strategy known as combo-therapy in the use of new azole antifungals recently designed. 47,48 Nevertheless further chemical modications will be carried out to synthetize a second generation of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives designed specically as EPIs of the pathogenic yeast C. albicans. Once again, compound 1d will be investigated for assessing the structural importance of its benzhydryl moiety (e.g.…”