Discovery of efficient inhibitors against pyruvate dehydrogenase complex component E1 with bactericidal activity using computer aided design.

Abstract 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.