Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors

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dc.contributor.advisorJardine, Anwaren_ZA
dc.contributor.authorSehata, Majimi Jamesen_ZA
dc.date.accessioned2015-05-11T13:34:38Z
dc.date.available2015-05-11T13:34:38Z
dc.date.issued2014en_ZA
dc.descriptionIncludes bibliographical referencesen_ZA
dc.description.abstractThe emergence of multiple drug resistant (MDR) and extremely drug resistant (XDR) strains of Mycobacterium tuberculosis (M.tb) against the known anti-tuberculosis drug regimens has prompted the need to search for new anti-tubercular drugs. In this study we report the design and synthesis of a series of thiazolidinethione derivatives and substrate mimics, aimed at targeting the mycothiol biosynthetic pathway which is specific to mycobacteria. The strategy involved design of molecules that are expected to compete for the UDP-GlcNAc binding site of the glycosyltransferase (MshA) of M.tb. The bioactivity of the designed molecules against M.tb in cell free and whole cell assays serves as a basis for further inhibitor optimisation. Amongst the thiazolidinethione derivatives screened, compounds (Z)-5-(2,4-dichlorobenzylidene)-2-thioxothiazolidin-4-one (MJ3A) and 2-((Z)-5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (MJ7B) were found to be the most potent compounds with a MIC 50 of 10 μg/mL. In addition, substrate mimics were synthesized and screened for anti-tuberculosis activity. Substrate mimics displayed moderate activity, with exception of substrate mimic (4 -34) which displayed th e highest potency. Tunicamycin which is a known glycosyltransferase inhibitor displayed the highest potency against M.tb H37Rv whole cells by inhibiting cell growth with a MIC 50 of 5 μg/mL . Tunicamycin inhibits the transfer of GlcNAc-1-P from UDP-GlcNAc to polyprenyl monophosphates in a variety of organisms including Gram positive bacteria.en_ZA
dc.identifier.apacitationSehata, M. J. (2014). <i>Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/12772en_ZA
dc.identifier.chicagocitationSehata, Majimi James. <i>"Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2014. http://hdl.handle.net/11427/12772en_ZA
dc.identifier.citationSehata, M. 2014. Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Sehata, Majimi James AB - The emergence of multiple drug resistant (MDR) and extremely drug resistant (XDR) strains of Mycobacterium tuberculosis (M.tb) against the known anti-tuberculosis drug regimens has prompted the need to search for new anti-tubercular drugs. In this study we report the design and synthesis of a series of thiazolidinethione derivatives and substrate mimics, aimed at targeting the mycothiol biosynthetic pathway which is specific to mycobacteria. The strategy involved design of molecules that are expected to compete for the UDP-GlcNAc binding site of the glycosyltransferase (MshA) of M.tb. The bioactivity of the designed molecules against M.tb in cell free and whole cell assays serves as a basis for further inhibitor optimisation. Amongst the thiazolidinethione derivatives screened, compounds (Z)-5-(2,4-dichlorobenzylidene)-2-thioxothiazolidin-4-one (MJ3A) and 2-((Z)-5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (MJ7B) were found to be the most potent compounds with a MIC 50 of 10 μg/mL. In addition, substrate mimics were synthesized and screened for anti-tuberculosis activity. Substrate mimics displayed moderate activity, with exception of substrate mimic (4 -34) which displayed th e highest potency. Tunicamycin which is a known glycosyltransferase inhibitor displayed the highest potency against M.tb H37Rv whole cells by inhibiting cell growth with a MIC 50 of 5 μg/mL . Tunicamycin inhibits the transfer of GlcNAc-1-P from UDP-GlcNAc to polyprenyl monophosphates in a variety of organisms including Gram positive bacteria. DA - 2014 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors TI - Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors UR - http://hdl.handle.net/11427/12772 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/12772
dc.identifier.vancouvercitationSehata MJ. Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2014 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/12772en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.titleSynthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitorsen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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