文献类型：期刊文献

英文题名：Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

作者：Zhang, Letian[1];Wu, Wende[1];Li, Zhong[1];Xu, Xiaoyong[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Sch Pharm, Shanghai 200237, Peoples R China

年份：2023

卷号：71

期号：28

起止页码：10575

外文期刊名：JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY

收录：;EI(收录号：20233014453272);WOS:【SCI-EXPANDED(收录号:WOS:001025886500001)】；

基金：This work was financial supported by the National Natural Science Foundation of China (no. 21672061). The authors are very thankful to GreenTech Laboratory (Building 2, No, Shunqing Road, Songjiang District, Shanghai) for the discussion of in vivo activity evaluation. Many thanks to our colleagues (Meijun Chen, Jiazhen Xu, Xujuan Sun, Wen Fu) for their help.

语种：英文

外文关键词：aminocyclobutanecarboxylic acid; SDHIs; conformationalrestriction; antifungal activity; SEM; DFT; MEP; molecular docking

摘要：The conformational restriction switch concept has beenadoptedas a major tool for structural optimization of pharmaceuticals inorder to expand the chemical structure scope and improve therapeuticactivity against specific proteins. Several of the 1-aminocyclobutanecarboxylicacid derivatives produced in this way exhibited satisfactory antifungalactivity in vitro compared with positive control boscalid. In vitroantifungal tests revealed that compound A21 had comparable,even higher antifungal activity against Rhizoctoniasolani (R.s., EC50 = 0.03 mg/L) and Botrytis cinerea (B.c., EC50 = 0.04mg/L) than fluxapyroxad (R.s., EC50 = 0.02 mg/L; B.c., EC50 = 0.20 mg/L) and boscalid (R.s., EC50 = 0.29 mg/L; B.c., EC50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activityagainst porcine SDH, its IC50 value was 3.73 & mu;M,which has considerable potency compared with fluxapyroxad (IC50 = 3.76 & mu;M). The mode of action was determined usingSEM and membrane potential research. The effects of the substituentsteric hindrance, electrostatic property, hydrophobicity, and hydrogen-bondfields on structure-activity relationships were elaboratedby the reliable models of comparative molecular field analysis andcomparative molecular similarity index analysis. Furthermore, densityfunctional theory simulations, molecule electrostatic potential, andmolecular docking were also used to study the probable binding modeof target compounds with flexible fragments. The results showed thatthe scaffold of 1-aminocyclobutanecarboxylic acid derivatives couldbe used as lead for discovering new succinate dehydrogenase inhibitors.