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Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis
Includes bibliographical references
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| Main Author: | |
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2016
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| _version_ | 1867613753801965568 |
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| access_status_str | Open Access |
| author | Kumar, Malkeet |
| author2 | Chibale, Kelly |
| author_browse | Chibale, Kelly Kumar, Malkeet |
| author_facet | Chibale, Kelly Kumar, Malkeet |
| author_sort | Kumar, Malkeet |
| collection | Thesis |
| description | Includes bibliographical references |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/16703 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:41:09.968Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2016 |
| publishDateRange | 2016 |
| publishDateSort | 2016 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/16703 Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis Kumar, Malkeet Chibale, Kelly Chemistry Antimycobacterial drugs Mycobacterium tuberculosis Includes bibliographical references Tuberculosis (TB) is one of the major infectious diseases and epidemics in the world. It is responsible for severe morbidity and mortality rates, especially in poor and resource-deficient countries. According to the World Health Organization 2014 report, about one third of the world's population is infected with tuberculosis and about 10-15% is co-infected with HIV, which further complicates the TB epidemic. Tuberculosis claims 2-3 million lives every year and is one of the biggest social and financial burdens on many countries. The disease is treatable but has been hampered by the emergence of drug resistance in the causative bacterium, Mycobacterium tuberculosis (Mtb). Resistant strains of Mtb counter the efficacy of various anti-TB drugs via mechanisms that help it overcome the toxic and inhibitory effects of these drugs. These mechanisms include mutation, enzymatic drug degradation, target modification and drug efflux. Drug efflux by efflux pumps (EPs) is one of the major mechanisms responsible for the development of drug tolerance leading to the emergence of drug resistance. These efflux pumps are regulated by the house keeping proteins present in the cell membrane of Mtb and perform a pre-existing role of rescuing the Mtb from toxic agents. These EPs extrude structurally unrelated compounds from the cell including anti-TB drugs and reduce the drug concentration to sub-inhibitory levels and aid Mtb in developing resistance. Therefore, development of antimycobacterials that target EPs and reduce their activity can be a viable strategy to reduce the global TB burden and counter the emergence of resistance. Many strategies have been used to counter the EP-mediated resistance in Mtb. In this study, two strategies were employed: (i) the development of efflux pump inhibitors (EPIs) via structural modification of a known efflux pump inhibitor, verapamil (VER), and the development of hybrid efflux pump inhibitors (HEPIs) incorporating a VER motif; and (ii) the development of antimycobacterial agents based on covalent linking or attachment of efflux pump inhibitor moieties to an anti-TB drug. These agents are termed reversed anti-TB agents and are based on isoniazid for this study. 2016-02-02T14:43:51Z 2016-02-02T14:43:51Z 2015 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/16703 eng application/pdf Department of Chemistry Faculty of Science University of Cape Town |
| spellingShingle | Chemistry Antimycobacterial drugs Mycobacterium tuberculosis Kumar, Malkeet Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis |
| thesis_degree_str | Doctoral |
| title | Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis |
| title_full | Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis |
| title_fullStr | Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis |
| title_full_unstemmed | Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis |
| title_short | Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis |
| title_sort | design synthesis and biological evaluation of verapamil analogues reversed isoniazids and hybrid efflux pump inhibitors against mycobacterium tuberculosis |
| topic | Chemistry Antimycobacterial drugs Mycobacterium tuberculosis |
| url | http://hdl.handle.net/11427/16703 |
| work_keys_str_mv | AT kumarmalkeet designsynthesisandbiologicalevaluationofverapamilanaloguesreversedisoniazidsandhybrideffluxpumpinhibitorsagainstmycobacteriumtuberculosis |