Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 4, Pages 833-844Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.12.047
Keywords
Efflux pumps; Chemosensitizers; Macrophages; Efflux pump inhibitors; M. tuberculosis; Ethidium bromide
Funding
- University of Cape Town
- South African Medical Research Council (SAMRC)
- South African Research Chairs Initiative of the Department of Science and Technology
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University
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Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then 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 mu M, R5401-MIC99 <= 2.5 mu M, X_61-MIC99 <= 5 mu M) demonstrated the potential of the 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 mu M) and inhibition of EB efflux demonstrated by these compounds are encouraging. (C) 2017 Elsevier Ltd. All rights reserved.
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