Expanding the Chemical Space of Succinate Dehydrogenase Inhibitors via the Carbon-Silicon Switch Strategy
Expanding the Chemical Space of Succinate Dehydrogenase Inhibitors via the Carbon-Silicon Switch Strategy
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通过碳硅转换策略扩大琥珀酸脱氢酶抑制剂的化学空间
DOI：
10.1021/acs.jafc.0c07322
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发表时间：
2021-03-29
影响因子：
6.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Wei, Ge;Huang, Ming-Wei;Yang, Guang-Fu
碳硅开关策略已成为药物结构优化的关键技术，以拓宽化学空间，增加药物对靶蛋白的活性，并产生新的和可专利的先导化合物。氟贝胺是中国最近开发的一种很有前途的候选杀菌剂，其作用靶点是琥珀酸脱氢酶（SDH）。我们采用C-Si开关策略，合成了具有增强杀菌活性的新型SDH抑制剂，以扩大氟苯特仑的化学空间。与先导化合物氟苯特仑和阳性对照相比，由此形成的几种氟苯特仑-甲硅烷基衍生物对猪SDH表现出改善的杀真菌活性。在温室中进行的疾病控制实验表明，三甲基甲硅烷基取代的化合物W2显示出相当的杀真菌活性，甚至更高的杀真菌活性相比，苯并烯氟吡菌和氟虫酰胺，分别，即使在大豆锈病控制的低浓度为0.19 mg/L。田间试验表明，W2在100 mg/L浓度下对大豆锈病的防效略好于嘧菌酯，但低于苯并烯氟吡菌。计算结果表明，W2中的硅基取代的苯基部分可以与SDH形成强的货车范德华力（VDW）相互作用。我们的研究结果表明，C-Si开关策略是一种有效的方法，为开发新的SDH抑制剂。
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.