51119-87-0Relevant articles and documents
Design, synthesis and biological evaluation of 5?substituted sulfonylureas as novel antifungal agents targeting acetohydroxyacid synthase
Dai, Huanqin,Gao, Li,Li, Zhengming,Meng, Fanfei,Mi, Pengcheng,Ren, Jinzhou,Wei, Wei,Yu, Zhenwu
, (2022/03/23)
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) 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.
Design, synthesis and SAR study of novel sulfonylureas containing an alkenyl moiety
Wei, Wei,Cheng, Dandan,Liu, Jingbo,Li, Yuxin,Ma, Yi,Li, Yonghong,Yu, Shujing,Zhang, Xiao,Li, Zhengming
, p. 8356 - 8366 (2016/09/09)
A series of sulfonylurea compounds was designed and synthesized via introducing an alkenyl moiety into the aryl-5 position and most title compounds exhibited enhanced antifungal activities and limited herbicidal activities compared with chlorsulfuron. Then, a CoMSIA calculation for antifungal activities was carried out to establish a 3D-QSAR model in which a cross-validated q2 of 0.585 and a correlation coefficient r2 of 0.989 were obtained. The derived model revealed that hydrophobic and electrostatic fields were the two most important factors for antifungal activity. Structure optimization was performed according to the CoMSIA model and compound 9z was found to be as potent as chlorothalonil in vitro against C. cornigerum, the pathogen of the wheat sharp eyespot disease. In order to study the fungicidal mechanism, 9z was successfully docked into yeast AHAS using a flexible molecular docking method and the resulting binding pattern was similar to that of chlorimuron-ethyl, indicating that the antifungal activity of compounds 9 was probably due to the inhibition of fungal AHAS.
