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Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach

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.

Publication metadata

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


DOI: 10.3390/molecules25102387


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