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Design, synthesis and molecular modeling of novel N-acylhydrazone derivatives as pyruvate dehydrogenase complex E1 inhibitors

2013; Elsevier BV; Volume: 22; Issue: 1 Linguagem: Inglês

10.1016/j.bmc.2013.11.051

1464-3391

Junbo He, Lingling Feng, Jing Li, Rui-Juan Tao, Yanliang Ren, Jian Wan, Hong‐Wu He,

Amino Acid Enzymes and Metabolism

As potential inhibitors of pyruvate dehydrogenase complex E1 (PDHc-E1), a series of 19 1-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-methyl-N'-(substituent)benzylidene-1H-1,2,3-triazole-4-carbohydrazide 4 has been synthesized and tested for their PDHc-E1 inhibitory activity in vitro. Some of these compounds such as 4a, 4g, 4l, 4o, 4p, and 4q were demonstrated to be effective inhibitors by the bioassay of Escherichia coli PDHc-E1. SAR analysis indicated that the PDHc-E1 inhibitory activity could be further enhanced by optimizing the substituted groups in the parent compound. Molecular modeling study with compound 4o as a model was performed to evaluate docking. The results of modeling study suggested a probable inhibition mechanism.