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

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