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Lookup NU author(s): Dr Alistair BrownORCiD, Alaa Aljohani, Fatimah Alsalem, Dr Jason GillORCiD, Dr Jon Sellars
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection, particularly drug-resistant strains, are urgently required to tackle the global burden of this disease. Herein, we reported the synthesis of a novel series of N-substituted amino acid hydrazides, utilising a scaffold hopping approach within a library of anti-tubercular agents. Efficacy and selectivity were evaluated against three strains of Mtb (wild-type, isoniazid-resistant and rifampicin-resistant), and cytotoxicity against macrophages in vitro. The antibacterial activity and therapeutic index of these molecules were significantly affected by modifications with the N-substituents. Introduction of a 3,5-dinitroaryl moiety demonstrated enhanced antibacterial activity against all three strains of Mtb. In contrast, the inclusion of an imidazo [1,2-a]pyridine-3-carboxy moiety resulted in enhanced activity towards isoniazid mono-resistant Mtb relative to wild-type Mtb. Consequently, this scaffold hopping approach showed significant promise for exemplification of novel molecules with specific activity profiles against drug-resistant tuberculosis.
Author(s): Brown AK, Aljohani AKB, Alsalem FMA, Broadhead JL, Gill JH, Lu Y, Sellars JD
Publication type: Article
Publication status: Published
Journal: Molecules
Year: 2020
Volume: 25
Issue: 10
Pages: 2387-2411
Online publication date: 21/05/2020
Acceptance date: 15/05/2020
Date deposited: 21/05/2020
ISSN (print): 1431-5165
ISSN (electronic): 1420-3049
Publisher: MDPI AG
URL: https://doi.org/10.3390/molecules25102387
DOI: 10.3390/molecules25102387
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