Synthesis and bioevaluation of 1-phenylimidazole-4-carboxylic acid derivatives as novel xanthine oxidoreductase inhibitors

Abstract

As part of a continuing study, we designed and synthesized four series of 1-phenylimidazole-4-carboxylic acid derivatives as xanthine oxidoreductase (XOR) inhibitors, evaluated their in vitro inhibitory potencies against XOR and hypouricemic effects in mice, and determined their structure-activity relationships (SARs). Most of the compounds exhibited in vitro XOR inhibition at the nanomolar level. In comparison to febuxostat (half-maximal inhibitory concentration [IC50] value of 7.0 nM), compounds Ie and IVa exhibited the most promising XOR inhibitory effects with IC50 values of 8.0 and 7.2 nM, respectively. In the potassium oxonate/hypoxanthine-induced acute and long-term hyperuricemia mouse models, compounds Ie and IVa displayed significant hypouricemic potencies (P < 0.05), that were slightly weaker than and similar to febuxostat, respectively. More interestingly, both compounds showed a capacity to improve kidney damage by decreasing creatinine and urea nitrogen levels compared to the long-term hyperuricemia mouse group (P < 0.05), while febuxostat showed no significant effect.