Computer aided optimization of lead compounds is of great significance to the design and discovery of new agrochemicals. A series of 2,6-dimethyl-4-aminopyrimidine acylhydrazones 6 was rationally designed as pyruvate dehydrogenase complex component E1 (PDHc-E1) inhibitors using computer aided drug design. Compounds in series 6 showed excellent inhibitory activity against Escherichia coli PDHc-E1, which was considerably higher than that of the lead compound A2. Compound 6l showed the best inhibitory activity (IC₅₀ = 95 nM). Molecular docking, site-directed mutagenesis, and enzymatic assays revealed that the compounds bound in a “straight” conformation in the active site of E. coli PDHc-E1. Compounds 6b, 6e, and 6l showed negligible inhibition against porcine PDHc-E1. The in vitro antibacterial activity indicated that 6a, 6d, 6e, 6g, 6h, 6i, 6m, and 6n exhibited 61%–94% inhibition against Ralstonia solanacearum at 100 μg/mL, which was better than commercial thiodiazole‑copper (29%) and bismerthiazol (55%). These results demonstrated that a lead structure for a highly selective PDHc-E1 inhibitor as a bactericide could be obtained using computer aided drug design.

先导化合物的计算机辅助优化对于新型农用化学品的设计和发现具有重要意义。使用计算机辅助药物设计将一系列 2,6-二甲基-4-氨基嘧啶酰基腙6合理设计为丙酮酸脱氢酶复合成分 E1 (PDHc-E1) 抑制剂。系列6中的化合物对大肠杆菌PDHc-E1表现出优异的抑制活性，其显着高于先导化合物A2的抑制活性。化合物6l显示出最好的抑制活性(IC ₅₀  = 95 nM)。分子对接、定点诱变和酶促测定表明，这些化合物在活性位点以“直”构象结合。大肠杆菌PDHc-E1。化合物6b、6e和6l对猪PDHc-E1的抑制作用可忽略不计。体外抗菌活性表明，6a、6d、6e、6g、6h、6i、6m和6n对100 μg/mL 的青枯菌有61%~94% 的抑制作用，优于商业硫二唑铜（29%） ) 和双甲噻唑 (55%)。这些结果表明，可以使用计算机辅助药物设计获得作为杀菌剂的高选择性 PDHc-E1 抑制剂的先导结构。