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Open AccessArticle

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

1
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
2
Arcinova, Taylor Drive, Alnwick NE66 2DH, UK
3
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
4
School of Pharmacy, Faculty of Medical Sciences, King George VI Building, Newcastle upon Tyne NE1 7RU, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Molecules 2020, 25(10), 2387; https://doi.org/10.3390/molecules25102387
Received: 22 April 2020 / Revised: 13 May 2020 / Accepted: 15 May 2020 / Published: 21 May 2020
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. View Full-Text
Keywords: antibacterial; Mycobacterium tuberculosis; amino acid; hydrazide; Q203; Naphthalene; Quinoline; scaffold hopping antibacterial; Mycobacterium tuberculosis; amino acid; hydrazide; Q203; Naphthalene; Quinoline; scaffold hopping
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MDPI and ACS Style

Brown, A.K.; Aljohani, A.K.B.; Alsalem, F.M.A.; Broadhead, J.L.; Gill, J.H.; Lu, Y.; Sellars, J.D. Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach. Molecules 2020, 25, 2387.

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