Design,synthesis and bioevaluation of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide derivatives as novel xanthine oxidase inhibitors |
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| Authors: | Lichao Zhang Sibo Wang Mingzheng Yang Ailong Shi He Wang Qi Guan Kai Bao Weige Zhang |
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| Institution: | 1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;2. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;3. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China |
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| Abstract: | In view of expanding the structure activity relationship of xanthine oxidase inhibitors, a series of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide/carboxylic acid derivatives were designed by molecular docking and synthesized. All the target compounds were evaluated for their in vitro XO inhibition by using febuxostat and allopurinol as the standard controls. Most of the hydrazide derivatives exhibited potency levels in the micromolar range. From the view of docking study, hydrazide derivatives bind to the active site of XO through a novel interaction mode, which is different from that of febuxostat bearing a carboxyl group. The most promising compound 8b was further subjected to kinetic analysis to deduce their modes of inhibition. |
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| Keywords: | Xanthine oxidase inhibitors Molecular docking 3-Oxo-6-aryl-2 3-dihydropyridazine-4-carbohydrazide Enzyme kinetic Lineweaver-Burk plot |
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