Design and Synthesis of Isobavachalcone Derivatives as Potential Dihydroorotate Dehydrogenase Inhibitors

Abstract Dihydroorotate dehydrogenase (DHODH) inhibitors have been reported to exhibit multi‐therapeutic potential due to their various pharmacological effects. As a result, the design and development of novel DHODH inhibitors is both necessary and an intriguing topic. Previous studies have demonstrated that Isobavachalcone, a natural compound isolated from Psoralea corylifolia , can efficiently inhibit the DHODH activity. Three primary series, designated A , B and C , were designed and synthesized based on the lead compound Isobavachalcone. The inhibitory activities of these compounds were evaluated using the Orotate Production Assay method, and the corresponding structure‐activity relationship (SAR) were thoroughly examined. Additionally, the interactions between the best active compounds and the DHODH protein were analyzed through a molecular docking study. These findings suggest that these derivatives have the potential to be promising candidates for the development of a new family of DHODH inhibitors.