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

Abstract：

:New 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 μM 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Chacko S,Boshoff HIM,Singh V,Ferraris DM,Gollapalli DR,Zhang M,Lawson AP,Pepi MJ,Joachimiak A,Rizzi M,Mizrahi V,Cuny GD,Hedstrom L

doi

10.1021/acs.jmedchem.7b01839

subject

Has Abstract

pub_date

2018-06-14 00:00:00

pages

4739-4756

issue

11

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

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