Design, Synthesis, and Antifungal Activity of 2,6-Dimethyl-4-aminopyrimidine Hydrazones as PDHc-E1 Inhibitors with a Novel Binding Mode

• DOI: 10.1021/acs.jafc.0c07701
• Publication Date: 2021-05-19T15:14:01Z
• Authors: Yuan Zhou; Shasha Zhang; Meng Cai; Kaixing Wang; Jiangtao Feng; Dan Xie; Lingling Feng; Hao Peng; Hongwu He
• Keywords: 0301 basic medicine; 0303 health sciences; Antifungal Agents; Hydrazones; Pyruvate Dehydrogenase Complex; 3. Good health; Molecular Docking Simulation; 03 medical and health sciences; Pyrimidines; Colletotrichum; Escherichia coli; Pyruvate Dehydrogenase (Lipoamide); Botrytis; Enzyme Inhibitors; Candida

A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones 5 were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds 5 strongly inhibited Escherichia coli (E. coli) PDHc-E1 (IC50 values 0.94-15.80 μM). As revealed by molecular docking, site-directed mutagenesis, enzymatic, and inhibition kinetic analyses, compounds 5 competitively inhibited PDHc-E1 and bound in a "straight" pattern at the E. coli PDHc-E1 active site, which is a new binding mode. In in vitro antifungal assays, most compounds 5 at 50 μg/mL showed more than 80% inhibition against the mycelial growth of six tested phytopathogenic fungi, including Botrytis cinerea, Monilia fructigena, Colletotrichum gloeosporioides, andBotryosphaeria dothidea. Notably, 5f and 5i were 1.8-380 fold more potent against M. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth of M. fructigena comparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.