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. 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.
- Authors:
-
[2];
[7];
[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
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID); South African Medical research Council (SAMRC); National Research Foundation (NRF) South Africa; U. S. Department of Health and Human Services; National Institutes of Health (NIH); USDOE
- OSTI Identifier:
- 1466338
- Grant/Contract Number:
- AC02-06CH11357; HHSN272200700058C; HHSN272201200026C
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 61; Journal Issue: 11; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
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., and Hedstrom, Lizbeth. Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents. United States: N. p., 2018.
Web. doi:10.1021/acs.jmedchem.7b01839.
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. Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents. United States. https://doi.org/10.1021/acs.jmedchem.7b01839
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., and Hedstrom, Lizbeth. Thu .
"Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents". United States. https://doi.org/10.1021/acs.jmedchem.7b01839. https://www.osti.gov/servlets/purl/1466338.
@article{osti_1466338,
title = {Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents},
author = {Chacko, Shibin and Boshoff, Helena I. M. and Singh, Vinayak and Ferraris, Davide M. and Gollapalli, Deviprasad R. and Zhang, Minjia and Lawson, Ann P. and Pepi, Michael J. and Joachimiak, Andrzej and Rizzi, Menico and Mizrahi, Valerie and Cuny, Gregory D. and Hedstrom, Lizbeth},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.7b01839},
journal = {Journal of Medicinal Chemistry},
number = 11,
volume = 61,
place = {United States},
year = {Thu May 10 00:00:00 EDT 2018},
month = {Thu May 10 00:00:00 EDT 2018}
}
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