Cong Zhou, Jiagao Cheng, Zhong Li
2021
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Abstract
Abstract Carbon–silicon bioisosteric replacements have been rarely investigated in crop protection research in recent years. We now report with the discovery of Sila-Cyflumetofen the first successful application of this discovery strategy in crop protection research in the last two decades. Sila-Cyflumetofen possesses higher intrinsic activity than Cyflumetofen, a new complex II acaricide recently introduced to the market, but has somewhat lower acaricidal activity in our laboratory tests. Our results demonstrate that the t-butyl-phenyl moiety of Cyflumetofen can be replaced by a trimethylsilyl-phenyl group with retention of high-level acaricidal activity and favorable pharmacological properties. In order to further optimize the biological activity, the first homology model of spider mite mitochondrial electron transport complex II or succinate–ubiquinone oxidoreductase has been developed as tool to enable the design of further analogues with improved activity. It was found that the active metabolites of Cyflumetofen AB-1 and Sila-Cyflumetofen Sila-AB-1 bind to the Qp site in the same binding pose and that both compounds form two H-bonds and a cation–π interaction with Trp 165, Tyr 433, and Arg 279, respectively. As a result of the pharmacophore model-guided optimization program, we found that the 4-t-butyl-phenyl, 4-trimethylsilyl-phenyl, and 3-trimethylsilyl-phenyl moieties deliver the best acaricidal activity. Modifications of the procide group of Sila-Cyflumetofen, performed in order to optimize the product characteristics such as physicochemical properties, pharmacokinetic behavior, and pharmacodynamic properties, resulted in the discovery of the silicon-containing beta-ketonitriles D2 and D3 which possess similar or even better acaricidal activity than Cyflumetofen in our screening tests. In summary, our research has demonstrated the high value of a carbon–silicon bioisosteric replacement strategy and may inspire other researchers to consider this powerful discovery strategy in their own research as well.