文献类型：期刊文献

英文题名：Design, synthesis and acaricidal activities of Cyflumetofen analogues based on carbon-silicon isosteric replacement

作者：Zhou, Cong[1];Cheng, Jiagao[1];Beadle, Ryan[2,4];Earley, Fergus G.[2];Li, Zhong[1];Maienfish, Peter[1,3]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Sch Pharm, Shanghai 200237, Peoples R China;[2]Syngenta Crop Protect AG, Jealotts Hill Res Ctr, Bracknell, Berks, England;[3]Syngenta Crop Protect AG, Schwarzwaldallee 215, CH-4002 Basel, Switzerland;[4]Univ York, Dept Biochem, York, N Yorkshire, England

年份：2020

卷号：28

期号：11

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000535809500009)】；

基金：This work was financially supported by National Key Research and Development Plan (2017YFD0200300), the National Natural Science Foundation of China (21572059, 21977030), and Innovation Program of Shanghai Municipal Education Commission (201701070002E00037). Acaricidal activities and enzyme inhibition were measured at Syngenta. The authors would like to thank Patrik Hoegger and Gemma Hough for performing the biological testing.

语种：英文

外文关键词：Discovery of Sila-Cyflumetofen; Beta-ketonitrile acaricide; Carbon-silicon bioisosteric replacement; Succinate ubiquinone oxidoreductase; Homology model; Spider mite SQR inhibition

摘要：The application of a carbon-silicon bioisosteric replacement strategy to find new acaricides with improved properties led to the discovery of Sila-Cyflumetofen 6B, a novel and highly potent acaricide. The essential t-butyl group in the beta-ketonitrile acaricide Cyflumetofen 6A could be swapped with the bioisosteric trimethyl-silyl group with retention of high level acaricidal activity and favourable pharmacological properties. Sila-Cyflumetofen 6B was found to possess similar preferred energy-minimized conformation and electrostatic potential surface compare to Cyflumetofen 6A. Herein we also report the development and application of the first homology model of the spider mite mitochondrial electron transport complex II (succinate ubiquinone oxidoreductase; SQR) and demonstrated that the active metabolite AB-1 of Cyflumetofen 6A and its sila-analogue Sila-AB-1 bind to the Qp site in same binding pose and that both compounds form two H-bonds and a cation-pi interaction with Trp 165, Tyr 433 and Arg 279, respectively. Furthermore, we also developed a new mode of action test for spider mite Complex II using cytochrome c as electron acceptor and blocking its re-oxidation by addition of KCN resulting in a sensitive and convenient colorimetric assay. This new method avoids the use of non-specific artificial electron acceptors and allows to measure SQR inhibition in crude extracts of Tetranychus urtice. In this assay Sila-AB-1, the intrinsically active metabolite of Sila-Cyflumetofen, 6A exhibited even a somewhat lower IC50 value than the metabolite of Cyflumetofen AB-1. Synthetic methodologies are described for the preparation of Sila-Cyflumetofen 6B and its active metabolite Sila-AB-1 which enable an efficient synthesis of these compounds in only 5 and 4 steps, respectively, from cheap commercial starting materials. Although the value of carbon-silicon bioisosteric replacements has already be demonstrated in the past it is to the best of our knowledge the first report of a successful application in crop protection research in the last two decades.