Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors

Abstract

This study mainly focused on the modification of the X² position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X² position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC₅₀ values ranging from 0.21µM to 26.13μM. Among them, compound 1s (IC₅₀=0.21μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X² position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4'-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure-activity relationships observed in this study.

Keywords: 1,2,3-Triazole; Hyperuricemia; Xanthine oxidase inhibitor.