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

Chacko, Shibin; Boshoff, Helena I.  M.; Singh, Vinayak; Ferraris, Davide M.; Gollapalli, Deviprasad R.; Zhang, Minjia; Lawson, Ann P.; Pepi, Michael J.; Joachimiak, Andrzej; Rizzi, Menico; Mizrahi, Valerie; Cuny, Gregory D.; Hedstrom, Lizbeth

doi:10.1021/acs.jmedchem.7b01839

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

Journal Article · Thu May 10 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b01839· OSTI ID:1466338

Chacko, Shibin ^[1]; ^[2]; Singh, Vinayak ^[3]; Ferraris, Davide M. ^[4]; Gollapalli, Deviprasad R. ^[1]; Zhang, Minjia ^[1]; Lawson, Ann P. ^[1]; Pepi, Michael J. ^[5]; Joachimiak, Andrzej ^[6]; Rizzi, Menico ^[4]; ^[7]; Cuny, Gregory D. ^[8]; ^[1]

Brandeis Univ., Waltham, MA (United States). Dept. of Biology
National Inst. of Allergy and Infectious Diseases, Bethesda, MD (United States). Tuberculosis Research Section
Univ. of Cape Town, Rondebosch, Cape Town (South Africa). Dept. of Drug Discovery and Development & Inst. of Infectious Disease and Molecular Medicine, H3D Drug Discovery and Development Centre
Univ. del Piemonte Orientale, Novara (Italy). Dipartimento di Scienze del Farmaco
Brandeis Univ., Waltham, MA (United States). Dept. of Chemistry
Univ. of Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases and Dept. of Biochemistry and Molecular Biology
Univ. of Cape Town (South Africa). MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research, Inst. of Infectious Disease and Molecular Medicine & Dept. of Pathology
Univ. of Houston, Houston, TX (United States). Dept. of Pharmacological and Pharmaceutical Sciences, College of Pharmacy

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. Here in this paper 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 mu 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID); National Research Foundation (NRF) South Africa; South African Medical research Council (SAMRC); U. S. Department of Health and Human Services; USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1466338

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 11 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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