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

Alistair K Brown,Fatimah M A Alsalem,Jason H Gill,Joseph L Broadhead,Yucheng Lu,Jonathan D Sellars,Ahmed K B Aljohani

doi:10.3390/molecules25102387

Alistair K Brown, Fatimah M A Alsalem + Show 5 more

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https://doi.org/10.3390/molecules25102387

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Abstract

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.

Highlights

The World Health OrganisatioN0 s (WHO) global tuberculosis report in 2019 recognises tuberculosis (TB) as a communicable disease responsible for a major cause of long term illness and continues to be one of the top ten causes of death worldwide from a single infectious agent [1]
Bedaquiline and the imidazo [1,2-a]pyridine-3-carboxy moiety. Both the amino acid and hydrazide moieties were locked within the structure, utilising
N-Boc amino acids and the corresponding hydrazide

Summary

Introduction

The World Health OrganisatioN0 s (WHO) global tuberculosis report in 2019 recognises tuberculosis (TB) as a communicable disease responsible for a major cause of long term illness and continues to be one of the top ten causes of death worldwide from a single infectious agent [1]. In 2018, an estimated ten million (range 9.0–11.1 million) new cases of TB infection were reported, equivalent to 132 cases per 100,000 population globally [2]. There is an ever-increasing number of infections from strains resistant to the front line anti-TB drugs—rifampicin (RIF) and isoniazid (INH), exacerbating further the global TB epidemic [1]. New drug molecules with novel modes of action are urgently required to address this increased disease burden and diminishing response to current therapies.

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