4.7 Article

Expanding the Chemical Space of Succinate Dehydrogenase Inhibitors via the Carbon-Silicon Switch Strategy

Journal

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
Volume 69, Issue 13, Pages 3965-3971

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jafc.0c07322

Keywords

succinate dehydrogenase inhibitors; silicon; soybean rust; docking

Funding

  1. National Key Research and Development Program of China [2018YFD0200100]
  2. National Natural Science Foundation of China [21977035, 21837001, 21772057]
  3. Key Research and Development Program of Hubei Province [2020BBA052]

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The carbon-silicon switch strategy has been effectively utilized to synthesize novel SDH inhibitors with enhanced fungicidal activity. The resulting compounds showed promising potential in disease control experiments and may serve as candidate fungicides in the future.
The carbon-silicon switch strategy has become a key technique for structural optimization of drugs to widen the chemical space, increase drug activity against targeted proteins, and generate novel and patentable lead compounds. Flubeneteram, targeting succinate dehydrogenase (SDH), is a promising fungicide candidate recently developed in China. We describe the synthesis of novel SDH inhibitors with enhanced fungicidal activity to enlarge the chemical space of flubeneteram by employing the C-Si switch strategy. Several of the thus formed flubeneteram-silyl derivatives exhibited improved fungicidal activity against porcine SDH compared with the lead compound flubeneteram and the positive controls. Disease control experiments conducted in a greenhouse showed that trimethyl-silyl-substituted compound W2 showed comparable and even higher fungicidal activities compared to benzovindiflupyr and flubeneteram, respectively, even with a low concentration of 0.19 mg/L for soybean rust control. Furthermore, compound W2 encouragingly performed slightly better control than azoxystrobin and was less active than benzovindiflupyr at the concentration of 100 mg/L against soybean rust in field trials. The computational results showed that the silyl-substituted phenyl moiety in W2 could form strong van der Waals (VDW) interactions with SDH. Our results indicate that the C-Si switch strategy is an effective method for the development of novel SDH inhibitors.

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