Abstract
Previous work led to the rational design, synthesis and testing of novel antifungal triazole analogues bearing alkynyl-methoxyl side chains. Tests of in vitro antifungal activity showed Candida albicans SC5314 and Candida glabrata 537 gave MIC values of ≤0.125 μg/mL for most of the compounds. Among these, compounds 16, 18, and 29 displayed broad-spectrum antifungal activity against seven human pathogenic fungal species, two fluconazole-resistant C. albicans isolates and two multi-drug resistant Candida auris isolates. Moreover, 0.5 μg/mL of 16, 18, and 29 was more effective than 2 μg/mL of fluconazole at inhibiting fungal growth of the strains tested. The most active compound (16) completely inhibited the growth of C. albicans SC5314 at 16 μg/mL for 24 h, affected biofilm formation and destroyed the mature biofilm at 64 μg/mL. Several Saccharomyces cerevisiae strains, overexpressing recombinant Cyp51s or drug efflux pumps, indicated 16, 18, and 29 targeted Cyp51 without being significantly affected by a common active site mutation, but were susceptible to target overexpression and efflux by both MFS and ABC transporters. GC-MS analysis demonstrated that 16, 18, and 29 interfered with the C. albicans ergosterol biosynthesis pathway by inhibition at Cyp51. Molecular docking studies elucidated the binding modes of 18 with Cyp51. The compounds showed low cytotoxicity, low hemolytic activity and favorable ADMT properties. Importantly, compound 16 showed potent in vivo antifungal efficacy in the G. mellonella infection model. Taken together, this study presents more effective, broad-spectrum, low toxicity triazole analogues that can contribute to the development of novel antifungal agents and help overcome antifungal resistance.
In this study, 27 novel triazole derivatives bearing alkynyl-methoxyl side chains were designed and synthesized based on our previous work. In vitro antifungal activity tests showed that most of the compounds exhibited excellent inhibition against Candida albicans SC5314 and Candida glabrata 537 (MIC ≤0.125 μg/mL). Among these, compounds 16, 18, and 29 displayed broad-spectrum antifungal activity and anti-drug-resistant fungal ability. Moreover, 16 inhibited the growth of C. albicans SC5314, reduced biofilm formation, and destroyed mature biofilm. Several Saccharomyces cerevisiae strains, overexpressing recombinant Cyp51s or drug efflux pumps, indicated these compounds targeted Cyp51 without being significantly affected by a common active site mutation but were susceptible to target overexpression and efflux by both MFS and ABC transporters. Importantly, 16 showed potent in vivo antifungal efficacy in the G. mellonella infection model. With more effective, broad-spectrum, anti-resistant, and low-toxicity triazole analogues that can contribute to the development of novel antifungal agents. [Display omitted]
•Most of our novel triazole analogues showed excellent activity against C. albicans SC5314 and C. glabrata 537 (MICs ≤0.125 μg/mL).•Compounds 16, 18 and 29 exhibited broad-spectrum antifungal activity against thirteen pathogenic fungi.•Compounds 16 reduced C. albicans biofilm formation and destroyed mature C. albicans biofilm.•Compounds 16, 18, and 29 targeted Cyp51 without being significantly affected by a common active site mutation, but were susceptible to target overexpression and efflux by both MFS and ABC transporters.•Compound 16 showed potent in vivo antifungal efficacy in the G. mellonella infection model.