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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.

Agre, N; Tawari, N; Maitra, A; Gupta, A; Munshi, T; Degani, M; Bhakta, S (2020) 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 (Basel), 9 (7). p. 368. ISSN 2079-6382 https://doi.org/10.3390/antibiotics9070368
SGUL Authors: Munshi, Tulika Kishanlal

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Abstract

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.

Item Type: Article
Additional Information: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Keywords: 5-nitrofuran, antibiotic resistance, arylamine N-acetyltransferase, tuberculosis, tuberculosis, antibiotic resistance, 5-nitrofuran, arylamineN-acetyltransferase
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Antibiotics (Basel)
ISSN: 2079-6382
Language: eng
Dates:
DateEvent
1 July 2020Published
30 June 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
PubMed ID: 32630175
Web of Science ID: WOS:000554082100001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112385
Publisher's version: https://doi.org/10.3390/antibiotics9070368

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