Diverse Development Approaches for Xanthine Oxidase Inhibitors: Synthetic Chemistry, Natural Product Chemistry, and Drug Repositioning

Xanthine oxidase (XOD) plays a crucial role in the biosynthesis of uric acid, and inhibiting its activity can effectively reduce the production of uric acid at its source. Currently, clinically used xanthine oxidase inhibitors (XODIs), such as allopurinol and febuxostat, are effective but associated with notable side effects. Allopurinol may induce hypersensitivity reactions, while febuxostat has been reported to potentially increase the risk of severe cardiovascular events. Therefore, the development of Xanthine oxidase inhibitors(XODIs) that lower serum uric acid levels through the inhibition of uric acid production has been a key focus in the research and development of anti-gout medications. This review is based on research literature from 2014 to 2025, sourced from multiple authoritative databases both domestically and internationally, including international databases such as Google Scholar, PubMed, Web of Science, Baidu Scholar, CNKI, Wanfang database. This review systematically summarizes 109 XODIs with urate-lowering or anti-gout pharmacological activities, categorized into chemical synthetic compounds, natural products and their derivatives, and repurposed drugs. The aim is to provide meaningful insights for the development of new therapeutic agents for gout and hyperuricemia. Notably, amides and carboxylic acids among chemically synthesized compounds exhibit promising prospects, while natural products with multiple mechanisms of uric acid reduction hold significant potential for the treatment of hyperuricemia.