Design, Synthesis, and Bio‐Evaluation of Salicylic Acid Derivatives as Potent XO Inhibitor

ABSTRACT Gout affects humans' quality of life and health. Xanthine oxidase is the most critical enzyme in the production of uric acid. So, targeting xanthine oxidase as a drug target for the treatment of gout is of great significance. This study aimed to salicylic acid derivatives as xanthine oxidase inhibitors with better potential for the treatment of hyperuricemia and gout. A total of thirteen salicylic acid derivatives were synthesized and evaluated as xanthine oxidase inhibitors. Six salicylic acid derivatives exhibited inhibitory activities against xanthine oxidase. Among them, compounds 5‐((4‐((4‐cyanobenzyl)oxy)‐3‐methoxybenzylidene)amino)‐2‐hydroxybenzoic acid ( 3d ), 2‐hydroxy‐5‐((4‐((4‐methoxybenzyl)oxy)‐3‐nitrobenzylidene)amino)benzoic acid ( 3k ), and 5‐((4‐((4‐cyanobenzyl)oxy)‐3‐nitrobenzylidene)amino)‐2‐hydroxybenzoic acid ( 3m ) possessed potent XO inhibitory activities which were better than that of the positive control allopurinol. Compound 3m showed the best xanthine oxidase inhibitory activity with an IC 50 value of 3.28 µM. Molecular docking results showed that the binding modes of compounds 3d , 3k , and 3m were similar to that of febuxostat. The ADME properties and toxicities of these compounds, which were examined using online tools, suggest that they may have pharmacological characteristics and safety. The results of the present study suggest the possible utility of salicylic acid derivatives as potent inhibitor of xanthine oxidase.