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

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.
Shibin Chacko,  Helena I M Boshoff 1,  Vinayak Singh 2,  Davide M Ferraris 3,  Deviprasad R Gollapalli,  Minjia Zhang,  Ann P Lawson,  Michael J Pepi,  Andrzej Joachimiak 4 5,  Menico Rizzi 3,  Valerie Mizrahi 6,  Gregory D Cuny 7,  Lizbeth Hedstrom
Affiliations

Affiliations

  • 1 Tuberculosis Research Section , National Institute of Allergy and Infectious Diseases , Bethesda , Maryland 20892 , United States.
  • 2 Department of Drug Discovery and Development & Institute of Infectious Disease and Molecular Medicine , H3D Drug Discovery and Development Centre, University of Cape Town , Rondebosch , Cape Town 7701 , South Africa.
  • 3 Dipartimento di Scienze del Farmaco , Universitá del Piemonte Orientale , Via Bovio 6 , 28100 Novara , Italy.
  • 4 Center for Structural Genomics of Infectious Diseases and Department of Biochemistry and Molecular Biology , University of Chicago , Chicago , Illinois 60557 , United States.
  • 5 Structural Biology Center, Biosciences , Argonne National Laboratory , 9700 S. Cass Avenue, Argonne , Illinois 60439 , United States.
  • 6 MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine & Department of Pathology , University of Cape Town , Anzio Road , Observatory 7925 , South Africa.
  • 7 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy , University of Houston , Health Building 2, 4849 Calhoun Road , Houston , Texas 77204 , United States.
PMID: 29746130 DOI: 10.1021/acs.jmedchem.7b01839
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.

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