Synthesis and biological evaluation of thiazolidine-2-thione derivatives as novel xanthine oxidase inhibitors

Abstract

Xanthine oxidase (XO) is a key enzyme in the generation and development of hyperuricemia. Thiazolidine-2-thione, a typical heterocyclic compound, have been widely used in the field of drug synthesis. In this study, a series of novel thiazolidine-2-thione derivatives were synthesized as XO inhibitors, and the XO inhibitory potencies of obtained compounds were evaluated by in vitro enzyme catalysis. The result shown that compound 6k behaved the strongest XO inhibitory activity with an IC50 value of 3.56 μmol/L, which was approximately 2.5-fold more potent than allopurinol. The structure-activity relationship revealed that the phenyl-sulfonamide group was indispensable for thiazolidine-2-thione derivatives to produce XO inhibitory activity. The enzyme inhibition kinetics analyses confirmed that compound 6k exerted a mixed-type XO inhibition. Additionally, the molecular docking results suggested that the 4-fluorophenyl-sulfonyl moiety could interact with Gly260 and Ile264 in the innermost part of the active pocket through 2 hydrogen bonds, while the thiazolidinethione moiety could form two hydrogen bonds with Glu263 and Ser347 in hydrophobic pockets. In summary, the results described above suggested that compound 6k could be a valuable lead compound for the treatment of hyperuricemia as a novel XO inhibitor.