Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents

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dc.contributor.advisorChibale, Kellyen_ZA
dc.contributor.authorMjambili, Faith Rizikien_ZA
dc.date.accessioned2014-08-20T19:27:35Z
dc.date.available2014-08-20T19:27:35Z
dc.date.issued2013en_ZA
dc.description.abstractTB patients show poor compliance to available drugs due to the costs, adverse side effects, and prolonged treatment, leading to multi-drug resistant (MDR), extensively drug resistant (XDR), and most recently totally drug resistant TB. Shared drug toxicities and drug interactions with antiretrovirals compound the problem. The rapid development of resistance to known antimalarials compared to the rate at which new agents are coming into the market still remains a big challenge is combating malaria. Currently, with resistance to ACTs having been documented in South-East Asia, the situation is dire as there is no ready alternative to these drugs. There is thus a heightened need for research towards the development of new anti-TB and anti-malarial drugs based on novel chemotypes. Towards addressing this need, SAR studies were conducted on the 2-amino-4-aryl thiazole scaffold by synthesizing a series of derivatives with different motifs at the various positions of the scaffold. These derivatives exhibited moderate antiplasmodial activity in the CQS strain of P. falciparum, and good antimycobacterial activity on the H37Rv strain of M.tb. A 2-pyridyl group at position 4 of the thiazole ring as well as a substituted phenyl at position 2 was found to be essential for antimycobacterial activity. However, the 2-pyridyl group was not essential for antiplasmodial activity while the substituted phenyl at position 2 was essential for antiplasmodial activity. The linker between these two groups affected antimycobacterial activity with little influence on the antiplasmodial activity. In addition structural modifications were performed on the ergoline backbone of metergoline, and a number of derivatives synthesized with different para substituted phenyls. These compounds exhibited moderate antiplasmodial activity in the CQS strain of P. falciparum, and moderate antimycobacterial activity on the H37Rv strain of M.tb. The presence of a substituted phenyl group attached to the nitrogen atom of the amine was found to be essential for antimycobacterial activity, however, this substituted phenyl group didn't confer optimum antimycobacterial activity as the compounds were less active than metergoline. The antiplasmodial activity of these compounds was better than that of metergoline and was enhanced by the hydrophobicity of the substituent on the phenyl ring. Changing the linker between the ergoline backbone and the substituted phenyl ring didn't have any significant effect on either the antimycobacterial or the antiplasmodial activity.en_ZA
dc.identifier.apacitationMjambili, F. R. (2013). <i>Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/6635en_ZA
dc.identifier.chicagocitationMjambili, Faith Riziki. <i>"Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2013. http://hdl.handle.net/11427/6635en_ZA
dc.identifier.citationMjambili, F. 2013. Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Mjambili, Faith Riziki AB - TB patients show poor compliance to available drugs due to the costs, adverse side effects, and prolonged treatment, leading to multi-drug resistant (MDR), extensively drug resistant (XDR), and most recently totally drug resistant TB. Shared drug toxicities and drug interactions with antiretrovirals compound the problem. The rapid development of resistance to known antimalarials compared to the rate at which new agents are coming into the market still remains a big challenge is combating malaria. Currently, with resistance to ACTs having been documented in South-East Asia, the situation is dire as there is no ready alternative to these drugs. There is thus a heightened need for research towards the development of new anti-TB and anti-malarial drugs based on novel chemotypes. Towards addressing this need, SAR studies were conducted on the 2-amino-4-aryl thiazole scaffold by synthesizing a series of derivatives with different motifs at the various positions of the scaffold. These derivatives exhibited moderate antiplasmodial activity in the CQS strain of P. falciparum, and good antimycobacterial activity on the H37Rv strain of M.tb. A 2-pyridyl group at position 4 of the thiazole ring as well as a substituted phenyl at position 2 was found to be essential for antimycobacterial activity. However, the 2-pyridyl group was not essential for antiplasmodial activity while the substituted phenyl at position 2 was essential for antiplasmodial activity. The linker between these two groups affected antimycobacterial activity with little influence on the antiplasmodial activity. In addition structural modifications were performed on the ergoline backbone of metergoline, and a number of derivatives synthesized with different para substituted phenyls. These compounds exhibited moderate antiplasmodial activity in the CQS strain of P. falciparum, and moderate antimycobacterial activity on the H37Rv strain of M.tb. The presence of a substituted phenyl group attached to the nitrogen atom of the amine was found to be essential for antimycobacterial activity, however, this substituted phenyl group didn't confer optimum antimycobacterial activity as the compounds were less active than metergoline. The antiplasmodial activity of these compounds was better than that of metergoline and was enhanced by the hydrophobicity of the substituent on the phenyl ring. Changing the linker between the ergoline backbone and the substituted phenyl ring didn't have any significant effect on either the antimycobacterial or the antiplasmodial activity. DA - 2013 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents TI - Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents UR - http://hdl.handle.net/11427/6635 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/6635
dc.identifier.vancouvercitationMjambili FR. Synthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agents. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2013 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/6635en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.titleSynthesis and biological evaluation of thiazole and metergoline derivatives as antimycobacterial and antiplasmodial agentsen_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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