Design and Synthesis of Isobavachalcone Derivatives as Potential Dihydroorotate Dehydrogenase Inhibitors

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.