Fragment Based Design, Synthesis and Biological Evaluation of Febuxostat-Indole Hybrids As Potent Xanthine Oxidase Inhibitors

Abstract

Novel xanthine oxidase inhibitors has been designed by using donepezil skeleton as template. Indole nucleus has been employed to target non-thiazole nucleus of febuxostat. Combination has been further optimized using Recore, Hyde and docking modules (Available with LeadIt: A drug design platform). Hybrid structures with most favorable interactions with active site of xanthine oxidase were synthesized and evaluated in vitro for xanthine oxidase inhibitory activity by using febuxostat as standard control. All synthesized hybrids showed potency levels in micromolar range. Most potent hybrid (A2) was then subjected to enzyme kinetic studies and showed mixed type inhibitory pattern. Molecular interactions with xanthine oxidase has been also elucidated which suggested that, A2 was sufficiently decorated with both hydrophilic and hydrophobic substitutions that perfectly block xanthine catalysis by xanthine oxidase.

Keywords: xanthine oxidase, molecular hybridization, molecular modelling, enzyme inhibition, fragment based design