In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking. The newly introduced acylhydrazone and N-phenylbenzamide moieties could form stronger interaction by hydrogen bond at the active site of E. coli PDHc-E1 compared with that of porcine PDHc-E1. A part of title compounds as potent PDHc-E1 inhibitors also exhibited notable antibacterial activity. In particular, 12e, 12f, 12g, 12o, and 19a exhibited 72–92% inhibition against Xanthomonas oryzae pv. Oryzae and Ralstonia solanacearum at 100 μg/mL, which was better than thiodiazole-copper (34 and 29%, respectively) and bismerthiazol (56 and 55%, respectively). The results proved that we could obtain effective bactericidal compounds as highly selective PDHc inhibitors by rational molecular design utilizing the binding model of active site of E. coli PDHc-E1.

为了获得PDHC-E1抑制剂以高选择性和功效，四个系列（7，12，15，和19 35新的4-氨基嘧啶衍生物）的合理设计和基于THDP在结合位点上合成大肠杆菌PDHC -E1。12，15，和19被证实是针对有效抑制剂大肠杆菌PDHC-E1。所选化合物12g，12i，15f和19a对猪PDHc-E1的抑制作用可忽略不计。要了解它们的选择性，抑制剂与大肠杆菌的相互作用通过分子对接研究了PDHc-E1或猪PDHc-E1。与猪PDHc-E1相比，新引入的酰基and和N-苯基苯甲酰胺部分在大肠杆菌PDHc-E1的活性位点可通过氢键形成更强的相互作用。部分标题化合物作为有效的PDHc-E1抑制剂也表现出显着的抗菌活性。特别是12e，12f，12g，12o和19a对米生黄单胞菌pv表现出72-92％的抑制作用。水稻和青枯菌浓度为100μg/ mL，优于硫代二唑铜（分别为34％和29％）和比美噻唑（分别为56％和55％）。结果证明，通过利用大肠杆菌PDHc-E1活性位点的结合模型进行合理的分子设计，可以得到作为高效选择性PDHc抑制剂的有效杀菌化合物。