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

• Published in: Journal of molecular structure 2022-07, Vol.1260, p.132756, Article 132756
• Main Authors: Meng, Fanfei, Mi, Pengcheng, Yu, Zhenwu, Wei, Wei, Gao, Li, Ren, Jinzhou, Li, Zhengming, Dai, Huanqin
• Format: Article
• Language: English
• Subjects: 5-substituted sulfonylureas; Acetohydroxyacid synthase; Antifungal activity; Drug resistance; SAR
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.132756

•The 5-substituted groups of the aryl in sulfonylureas have a key impact on inhibition bioactivity against fungi.•5-substituted sulfonylureas have much better inhibitory activities against fungi than those of Fluconazole (FCZ) and amphotericin B (AMB).•An unusual possible double-pocket binding model in the active site of C. albicans AHAS catalytic subunit is revealed.•The low energy gap value between the HOMOs and LUMOs contributes to maintenance or improvement of the inhibition bioactivity against fungi microbes. 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)