| Abstrakt: |
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 (IC 50 = 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. [Display omitted] • Seventeen novel 2,6-dimethyl-4-aminopyrimidine derivatives containing acylhydrazone moiety were designed using computer-aided drug design. • Compound 6l had a strong binding capacity for E. coli PDHc-E1. • Compounds in series 6 displayed highly selective between E. coli PDHc-E1 and mammal PDHc-E1. • The binding models for 6l and E. coli PDHc-E1 and porcine PDHc-E1 were defined. • Compounds 6a , 6d , 6e , 6g , 6h , 6i , 6m , and 6n can effectively against Ralstonia solanacearum at 100 μg/mL. [ABSTRACT FROM AUTHOR] |
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