Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors

In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1, 2, 4-triazol-1-y1)-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase (HsDHODH) for structural optimization. The co-crystal of HsDHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result, a series of novel triazole derivatives were designed and synthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H-1, 2, 4-triazol-1-y1)-furan-2-y1-methanone displayed high potency in the inhibition of HsDHODH with an IC₅₀ value of 1.50 μmol·L^-1. Meanwhile, the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1, 2, 4-triazole derivatives as HsDHODH inhibitors in the future.