Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase ( Hp IMPDH) inhibitors

Inosine 5′‐monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3‐triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH ( Hp IMPDH) and human IMPDH2 ( h IMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for Hp IMPDH and h IMPDH2 inhibition were 9–99.9% and 16–57%, respectively, at 10 μM concentration. The most potent Hp IMPDH inhibitor, 25c , exhibited IC 50 value of 1.27 μM with no h IMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c , may serve as a lead for further design and development of highly potent Hp IMPDH inhibitors.