Design, synthesis and biological evaluation of Helicobacter pylori inosine 5?-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2

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dc.contributor.author Shah, Chetan P.
dc.contributor.author Purushothaman, Gayathri
dc.contributor.author Thiruvenkatam, Vijay
dc.contributor.author Kirubakaran, Sivapriya
dc.contributor.author Juvale, Kapil
dc.contributor.author Kharkar, Prashant S
dc.date.accessioned 2019-04-24T06:26:18Z
dc.date.available 2019-04-24T06:26:18Z
dc.date.issued 2019-06
dc.identifier.citation Shah, Chetan P.; Purushothaman, Gayathri; Thiruvenkatam, Vijay; Kirubakaran, Sivapriya; Juvale, Kapil and Kharkar, Prashant S., "Design, synthesis and biological evaluation of Helicobacter pylori inosine 5′-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2", Bioorganic Chemistry, DOI: 10.1016/j.bioorg.2019.04.001, vol. 87, pp. 753-764, Jun. 2019. en_US
dc.identifier.issn 0045-2068
dc.identifier.uri https://doi.org/10.1016/j.bioorg.2019.04.001
dc.identifier.uri https://repository.iitgn.ac.in/handle/123456789/4411
dc.description.abstract Inosine 5′-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDHs, microbial IMPDHs are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated ≥70% HpIMPDH inhibition at 10 μM concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 µM) in the series. The study reaffirmed the utility of 5-aminoisobenzofuran-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.
dc.description.statementofresponsibility by Chetan P Shah, Gayathri Purushothaman, VijayThiruvenkatam, Sivapriya Kirubakaran, Kapil Juvale and Prashant S Kharkar
dc.format.extent vol. 87, pp. 753-764
dc.language.iso en en_US
dc.publisher Elsevier en_US
dc.title Design, synthesis and biological evaluation of Helicobacter pylori inosine 5?-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2 en_US
dc.type Article en_US
dc.relation.journal Bioorganic Chemistry


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