Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents
| Autor: | Lizbeth Hedstrom, Davide M. Ferraris, Shibin Chacko, Michael J. Pepi, Minjia Zhang, Helena I. Boshoff, Deviprasad R. Gollapalli, Vinayak Singh, Valerie Mizrahi, Gregory D. Cuny, Andrzej Joachimiak, Ann P. Lawson, Menico Rizzi |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Guanine Antitubercular Agents Microbial Sensitivity Tests 01 natural sciences Article Mycobacterium tuberculosis Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound IMP Dehydrogenase Biosynthesis Cell Line Tumor Drug Discovery medicine Humans Structure–activity relationship Enzyme Inhibitors Inosine-5′-monophosphate dehydrogenase Inosine Benzoxazoles biology 010405 organic chemistry Chemistry Benzoxazole biology.organism_classification 0104 chemical sciences 030104 developmental biology Biochemistry Drug Design biology.protein Molecular Medicine medicine.drug Guanine salvage |
| Zdroj: | Journal of Medicinal Chemistry. 61:4739-4756 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01839 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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