isoliquiritigenin and Gout

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.

Topics: Animals; Benzimidazoles; Benzoxazoles; Cell Line; Disease Models, Animal; Gout; Humans; Hyperuricemia; Interleukin-1beta; Liver; Mice; Monocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Oxonic Acid; Rats; Structure-Activity Relationship; Synovial Membrane; Uric Acid; Xanthine Oxidase

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.

Topics: Amines; Animals; Benzoin; Benzoxazoles; Cell Line; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gout; Gout Suppressants; HEK293 Cells; Humans; Immunity, Innate; Liver; Male; Mice; Mice, Inbred Strains; Molecular Structure; Oximes; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Uric Acid; Xanthine Oxidase