Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 95, Issue 1, Pages 192-199Publisher
WILEY
DOI: 10.1111/cbdd.13624
Keywords
5-nitrothiophene; arylamine N-acetyltransferase inhibitors; HT-SPOTi assay; multidrug efflux pump inhibitors; multitargeted antimycobacterials
Funding
- Wellcome Trust
- INSPIRE program, Department of Science & Technology, New Delhi, India [IF140945]
- Global Challenges Research Fund
- Commonwealth Scholarship Commission [INCN-2017-287]
- Birkbeck Anniversary Fund
- MRC [G0802079] Funding Source: UKRI
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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.
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