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Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase ( Hp IMPDH) inhibitors
Author(s) -
Sahu Niteshkumar U.,
Purushothaman Gayathri,
Thiruvenkatam Vijay,
Kharkar Prashant S.
Publication year - 2019
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21467
Subject(s) - imp dehydrogenase , inosine , biochemistry , chemistry , helicobacter pylori , inosine monophosphate , mycobacterium tuberculosis , biosynthesis , dehydrogenase , enzyme , ic50 , nucleotide , pharmacology , in vitro , stereochemistry , biology , tuberculosis , medicine , surgery , pathology , gene , transplantation , mycophenolic acid , genetics
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.