Design, synthesis and biological evaluation of 5‑substituted sulfonylureas as novel antifungal agents targeting acetohydroxyacid synthase

Abstract

Acetohydroxyacid synthase (AHAS; EC2.2.1.6) exists solely in plants and microbes, and the biosynthesis of branched chain amino acids (valine, leucine and isoleucine) gets obstructed when sulfonylureas bind to AHAS catalytic subunit active site, which leads to the inability to synthesize these proteins and eventually causes the death of plants and microbes. Thus, the AHAS is also a promising antifungal target. Nowadays, there is an urgent need to discover new potential targets and chemical structures to prevent the growing morbidity and mortality of fungal infections and the emergence of severe antifungal drug resistance. In this work, 36 target compounds were designed and synthesized and several 5-substituted sulfonylureas possess much better antifungal activities than those of Fluconazole (FCZ) and amphotericin B (AMB). The most potent of these were L10, L23 and L31 with inhibition constants (Ki) determined in the range of 5.6∼9.6 nM for C. albicans AHAS and MICs(The MIC was determined as the drug concentration that inhibits fungal growth by >90% relative to the corresponding drug-free growth control) <0.05∼0.78 µg/mL for C. albicans SC 5314, 17# and 2# (17# and 2# are two clinically isolated FCZ-resistant strains of C. albicans), S. cerevisiae SCXH1549 and C. parapsilosis ATCC22019 in YNB (yeast nitrogen base) media at 72 h post-treatment. Using the same media, the commercial MICs of FCZ and AMB were only determined in the range of 0.25∼5 µg/mL for the five strains at 24 h post-treatment. In order to elaborate the structure-activity relationship (SAR) a proposed double-pocket binding mode was simulated via molecular docking. The energy gap between the HOMOs and LUMOs of selected compounds showed that the 5-substituted groups of sulfonylureas have key impact on the antimicrobial bioactivity.