Publication: Expanding benzoxazole-based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor structure-activity as potential antituberculosis agents
Chacko, S Boshoff, H.I.M Singh, V Ferraris, D.M Gollapalli, D.R Zhang, M Lawson, A.P Pepi, M.J Joachimiak, A Rizzi, M
Chacko, S
Boshoff, H.I.M
Singh, V
Ferraris, D.M
Gollapalli, D.R
Zhang, M
Lawson, A.P
Pepi, M.J
Joachimiak, A
Rizzi, M
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.
Description
Date
2018-05-10
Journal Title
Journal ISSN
Volume Title
Publisher
ACS Publications
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
Inosine 5′-Monophosphate Dehydrogenase (IMPDH),Antituberculosis agents,Inhibitors,Reaction products,SDG-03 Good health and well-being
Citation
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. Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure-Activity As Potential Antituberculosis Agents. J Med Chem. 2018 Jun 14;61(11):4739-4756. doi: 10.1021/acs.jmedchem.7b01839.