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Open AccessArticle

3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria

1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, India
2
Department of Biological Sciences, The Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK
3
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK
4
Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK
*
Authors to whom correspondence should be addressed.
Authors have contributed equally.
Antibiotics 2020, 9(7), 368; https://doi.org/10.3390/antibiotics9070368
Received: 11 May 2020 / Revised: 28 June 2020 / Accepted: 30 June 2020 / Published: 1 July 2020
In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria-infected macrophage model. The derivatives were assessed for their potential to inhibit mycobacterial arylamine N-acetyltransferase (NAT) and were identified as good inhibitors of recombinant mycobacterial NAT, a novel target essential for the intracellular survival of M. tuberculosis. This study provided hits for designing new potent and selective antituberculosis leads, having mycobacterial NAT inhibition as their possible endogenous mechanisms of action. View Full-Text
Keywords: tuberculosis; antibiotic resistance; 5-nitrofuran; arylamine N-acetyltransferase tuberculosis; antibiotic resistance; 5-nitrofuran; arylamine N-acetyltransferase
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MDPI and ACS Style

Agre, N.; Tawari, N.; Maitra, A.; Gupta, A.; Munshi, T.; Degani, M.; Bhakta, S. 3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria. Antibiotics 2020, 9, 368.

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