Abstract
Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were designed and synthesized in an effort to obtain antifungals with potent, broad-spectrum activity that are less susceptible to resistance. Most of these compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.125 μg/mL to 0.5 μg/mL. Use of recombinant Saccharomyces cerevisiae strains showed compounds 7 and 10 overcame the overexpression and resistant-related mutations in ERG11 of S. cerevisae and several pathogenic Candida spp. Despite being substrates of the C. albicans and Candida auris Cdr1 drug efflux pumps, compounds 7 and 10 showed moderate potency against five fluconazole (FCZ)-resistant fungi with MIC values from 2.0 μg/mL to 16.0 μg/mL. Growth kinetics confirmed compounds 7 and 10 had much stronger fungistatic activity than FCZ. For C. albicans, compounds 7 and 10 inhibited the yeast-to-hyphae transition, biofilm formation and destroyed mature biofilm more effectively than FCZ. Preliminary mechanism of action studies showed compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption. Further investigation of these novel triazole derivatives is also warranted by their predicted ADMET properties and low cytotoxicity.
In this study, twenty-nine novel triazole derivatives bearing pyrazole-methoxyl side chains were designed and synthesized based on our previous work. Most compounds exhibited moderated to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.125 μg/mL to 0.5 μg/mL. Among them, representative compounds 7 and 10 displayed broad-spectrum inhibitory effect against seven human pathogenic fungi, two fluconazole-resistant C. albicans and three muti-drug resistant Candida auris isolates. Importantly, by using of the recombinant Saccharomyces cerevisiae strains, we revealed that compounds 7 and 10 overcame the overexpression or the resistant-related mutations in ERG11 in the pathogenic Candida spp. Time-growth studies confirmed that the highly active compounds 7 and 10 had better fungistatic activity than FCZ. Moreover, compounds 7 and 10 effectively inhibited yeast-to-hyphae transition and biofilm formation, and destroyed the mature biofilm. Preliminary mechanism of action studies indicated that our synthesized compounds acted on the ergosterol biosynthesis pathway via inhibition of fungal Erg11, ultimately leading to cell membrane disruption. Collectively, the above findings implied that these novel triazole derivatives with more effective, proper ADMET properties and low cytotoxicity can contribute to overcome antifungal resistance and warrant further investigation. [Display omitted]
•Most of target compounds exhibited moderated to excellent activity against C. albicans, C. neoformans, C. glabrata and C. parapsilosis.•Compounds 7 and 10 displayed broad-spectrum inhibitory effect against tested pathogenic fungi.•Compounds 7 and 10 overcame the overexpression or the resistant-related mutations in ERG11 in the pathogenic Candida spp.•Compounds 7 and 10 effectively inhibited yeast-to-hyphae transition and biofilm formation, and destroyed the mature biofilm.•Compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption.