Design, synthesis, and evaluation of tricyclic compounds containing phenyl-tetrazole as XOR inhibitors

Based on analyses of the interaction between febuxostat and xanthine oxidoreductase (XOR), tetrazole was used to replace the carboxyl-thiazole fragment of febuxostat using a bioelectronic isosteric strategy. Three series of compounds were designed. The inhibitory activity against XOR of all compounds was evaluated and their structure-activity relationships determined. The inhibitory activity against XOR of compounds I was weak, with a half-maximal inhibitory concentration (IC₅₀) value > 10 μmol, whereas the inhibitory activity of compounds II and III was increased significantly, among which compounds IIIa (IC₅₀ = 26.3 ± 1.21 nM) and IIIc (IC₅₀ = 29.3 ± 0.88 nM) were the best. Molecular docking showed that tetrazole could enter the active cavity instead of a carboxyl group and retain most of the interaction between febuxostat and XOR. For compounds III, the hydrogen bonds with Asn768 and Thr1010 of XOR were absent, but some new interactions were introduced to improve potency. A potassium oxazinate/hypoxanthine-induced model of acute hyperuricemia in mice also showed a significant hypouricemia effect of compounds IIIa, IIIc, and IIIe (P < 0.01), which was consistent with the results of inhibition in vitro. In conclusion, we identified a promising XOR inhibitor and provided new ideas for the design of XOR inhibitors.