Reversed Isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis

Publication date: Available online 29 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Malkeet Kumar, Kawaljit Singh, Andile H. Ngwane, Fahreta Hamzabegovic, Getahun Abate, Bienyameen Baker, Ian Wiid, Daniel F. Hoft, Peter Ruminski, Kelly Chibale
Novel reversed isoniazid (RINH) agents have been synthesized by covalently linking isoniazid with various efflux pump inhibitors (EPIs) cores and their structural motifs. These RINH agents were evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M. tuberculosis (4a-c, 7 and 8; H37Rv-MIC99 ≤ 1.25 µM, R5401-MIC99 ≤ 2.5 µM, X_61- MIC99 ≤ 5 µM) demonstrated the viability of reversed anti-TB agent strategy towards the development of novel anti-mycobacterial agents to address the rapidly growing issue of resistance. Further, macrophage activity with >90% inhibition by 1a-c and 3b (MIC90 ≤ 13.42 µM) and inhibition of EB efflux demonstrated by these compounds are encouraging.

Graphical abstract

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