Paper
Design, Synthesis, and Antifungal Activity of 2,6-Dimethyl-4-aminopyrimidine Hydrazones as PDHc-E1 Inhibitors with a Novel Binding Mode.
Published May 19, 2021 · DOI · Yuan Zhou, Shasha Zhang, Meng-Na Cai
Journal of agricultural and food chemistry
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Abstract
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 inhibitedEscherichia 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 againstM. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth ofM. fructigenacomparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.
Novel 2,6-dimethyl-4-aminopyrimidine hydrazones show potential commercial value for controlling peach brown rot caused by Monilia fructigena, with a new binding mode and strong inhibitory effect on phytopathogenic fungi.
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