Design, synthesis, and biological evaluation of novel substituted benzamide derivatives bearing a 1,2,3-triazole moiety as potent human dihydroorotate dehydrogenase inhibitors

Abstract

A novel series of substituted benzamide derivatives bearing a 1,2,3-triazole moiety were designed and synthesized by click chemistry. Human dihydroorotate dehydrogenase inhibition assay was used to evaluate the synthesized compounds as potent hDHODH inhibitors. Most compounds showed moderate to significant potency, accompanied with a suitable clogD_7.4 value and compounds 4d, 4o, and 5j effectively inhibited the activity of hDHODH with IC₅₀ values of 2.1, 2.1 and 1.5 μM, respectively. Compound 4o also effectively suppressed proliferation of the activated PBMCs. The study of structure-activity relationships also revealed that a suitable substitution on para-position of terminal phenyl ring was crucial for high activity. Together, the most promising compound 4o might serve as a novel hDHODH inhibitors for further investigation.

Keywords: 1,2,3-Triazole; Bioisosterism; Human dihydroorotate dehydrogenase (hDHODH) inhibitors; Immunosuppressive activity; Scaffold-hopping.