Reversed isoniazids: Design,synthesis and evaluation against Mycobacterium tuberculosis |
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| Authors: | Malkeet Kumar Kawaljit Singh Andile H Ngwane Fahreta Hamzabegovic Getahun Abate Bienyameen Baker Ian Wiid Daniel F Hoft Peter Ruminski Kelly Chibale |
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| Institution: | 1. Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa;2. 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, P.O. Box 241, Cape Town 8000, South Africa;3. Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University, 1100 S. Grand Blvd, 63104 MO, USA;4. Department of Molecular Biology, Saint Louis University, 1100 S. Grand Blvd, 63104 MO, USA;5. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa;6. Centre for World Health and Medicine, Saint Louis University, 1100 S. Grand Blvd, 63104 MO, USA;g. South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa |
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| Abstract: | 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?µM, R5401-MIC99 ≤2.5?µM, X_61-MIC99 ≤5?µM) 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?µM) and inhibition of EB efflux demonstrated by these compounds are encouraging. |
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| Keywords: | Efflux pumps Chemosensitizers Macrophages Efflux pump inhibitors Ethidium bromide |
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