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

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.

(E)-Methyl 3-{3-[(4-bromo-phen-oxy)-methyl]phen-yl}acrylate.

In the mol-ecule of the title compound, C(17)H(15)BrO(3), the rings make a dihedral angle of 75.54 (17)°. In the crystal structure, inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers, and the π-stacked dimers inter-act with neighbouring dimers via C-H⋯π stacking inter-actions.