Exploration of 5‐(5‐nitrothiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazoles as selective, multitargeted antimycobacterial agents
| Autor: | Arundhati Maitra, Tulika Munshi, Mihir Khambete, Antima Gupta, Sanjib Bhakta, Mariam S. Degani, Neha Agre |
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| Rok vydání: | 2019 |
| Předmět: |
Arylamine N-Acetyltransferase
Cell Survival Drug Evaluation Preclinical Pharmacology 01 natural sciences Biochemistry Cell Line Mice chemistry.chemical_compound Bacterial Proteins Drug Discovery medicine Animals Humans Enzyme Inhibitors Mode of action Cytotoxicity Mycobacterium bovis Bacteria biology 010405 organic chemistry Organic Chemistry Isoniazid biology.organism_classification Anti-Bacterial Agents High-Throughput Screening Assays 0104 chemical sciences 3. Good health 010404 medicinal & biomolecular chemistry chemistry Pyrazoles Molecular Medicine Efflux Growth inhibition Antibacterial activity medicine.drug |
| Zdroj: | Chemical Biology & Drug Design. 95:192-199 |
| ISSN: | 1747-0285 1747-0277 |
| Popis: | We report the biological evaluation of 5-(5-nitrothiophen-2-yl)-4,5-dihydro-1H-pyrazole derivatives against bacteria, eukaryotic cell lines and the assessment of their mechanisms of action to determine their prospects of being developed into potent antituberculosis agents. The compounds were evaluated for their antibacterial property against Mycobacterium tuberculosis H37Rv, multidrug-resistant M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus using high-throughput spot-culture growth inhibition assay. They were found to be selective toward slow-growing mycobacteria and Gram-positive bacteria. In M. bovis BCG, they exhibited a bactericidal mode of action. Cytotoxicity was assessed in human THP-1 and murine RAW 264.7 cell lines, and the compounds showed a lower cytotoxicity potential when compared with their antibacterial activity. They were found to be excellent whole-cell efflux pump inhibitors of the mycobacterial surrogate M. aurum, performing better than known efflux pump inhibitor verapamil. The 5-nitrothiophene moiety was identified for the first time as a prospective inhibitor scaffold of mycobacterial arylamine N-acetyltransferase enzyme, which is the key enzyme in metabolizing isoniazid, a first-line antituberculosis drug. The two aforementioned findings make the compounds potential hits in the development of adjunctive tuberculosis therapy. |
| Databáze: | OpenAIRE |
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