Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis

 

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dc.contributor.advisor Chibale, Kelly en_ZA
dc.contributor.author Kumar, Malkeet en_ZA
dc.date.accessioned 2016-02-02T14:43:51Z
dc.date.available 2016-02-02T14:43:51Z
dc.date.issued 2015 en_ZA
dc.identifier.citation Kumar, M. 2015. Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/16703
dc.description Includes bibliographical references en_ZA
dc.description.abstract 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. en_ZA
dc.language.iso eng en_ZA
dc.subject.other Chemistry en_ZA
dc.subject.other Antimycobacterial drugs en_ZA
dc.subject.other Mycobacterium tuberculosis en_ZA
dc.title Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis en_ZA
dc.type Doctoral Thesis
uct.type.publication Research en_ZA
uct.type.resource Thesis en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Science en_ZA
dc.publisher.department Department of Chemistry en_ZA
dc.type.qualificationlevel Doctoral
dc.type.qualificationname PhD en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Kumar, M. (2015). <i>Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/16703 en_ZA
dc.identifier.chicagocitation Kumar, Malkeet. <i>"Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2015. http://hdl.handle.net/11427/16703 en_ZA
dc.identifier.vancouvercitation Kumar M. Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2015 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/16703 en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Kumar, Malkeet AB - 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. DA - 2015 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis TI - Design, synthesis and biological evaluation of verapamil analogues, reversed isoniazids and hybrid efflux pump inhibitors against Mycobacterium tuberculosis UR - http://hdl.handle.net/11427/16703 ER - en_ZA


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