Expanding Benzoxazole-Based Inosine 5?-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

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dc.contributor.authorChacko, Shibin
dc.contributor.authorBoshoff, Helena I. M.
dc.contributor.authorSingh, Vinayak
dc.contributor.authorFerraris, Davide M.
dc.contributor.authorGollapalli, Deviprasad R.
dc.contributor.authorZhang, Minjia
dc.contributor.authorLawson, Ann P.
dc.contributor.authorPepi, Michael J.
dc.contributor.authorJoachimiak, Andrzej
dc.contributor.authorRizzi, Menico
dc.contributor.authorMizrahi, Valerie
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorHedstrom, Lizbeth
dc.date.accessioned2020-03-10T17:30:51Z
dc.date.available2020-03-10T17:30:51Z
dc.date.issued2018-05
dc.description.abstractNew drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis (Mtb) inosine 5?-monophosphate dehydrogenase 2 (MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure–activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ?1 ?M can be achieved. The antibacterial activity of the most promising compound, 17b (Q151), is derived from the inhibition of MtbIMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of 17b, alleviating the concern that guanine salvage can protect Mtb in vivo. These findings suggest that MtbIMPDH2 is a vulnerable target for tuberculosis.
dc.identifier.citationCopyright 2019 Journal of Medicinal Chemistry. This is a post-print version of a published paper that is available at: https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01839. Recommended citation: Chacko, Shibin, Helena IM Boshoff, Vinayak Singh, Davide M. Ferraris, Deviprasad R. Gollapalli, Minjia Zhang, Ann P. Lawson et al. "Expanding Benzoxazole-Based Inosine 5?-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents." Journal of medicinal chemistry 61, no. 11 (2018): 4739-4756. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.
dc.identifier.urihttps://hdl.handle.net/10657/5931
dc.language.isoen_US
dc.publisherJournal of Medicinal Chemistry
dc.titleExpanding Benzoxazole-Based Inosine 5?-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents
dc.typeArticle

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