Synthesis and structure-activity relationship studies of novel anti-infectives for cross screening in tuberculosis and malaria disease models

 

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dc.contributor.advisor Chibale, Kelly en_ZA
dc.contributor.author Gessner, Richard Klaus en_ZA
dc.date.accessioned 2014-08-13T14:26:19Z
dc.date.available 2014-08-13T14:26:19Z
dc.date.issued 2008 en_ZA
dc.identifier.citation Gessner, R. 2008. Synthesis and structure-activity relationship studies of novel anti-infectives for cross screening in tuberculosis and malaria disease models. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/6308
dc.description Includes abstract. en_ZA
dc.description Includes bibliographical references (p. 205). en_ZA
dc.description.abstract Some 12-16 hours after the invasion of the human erythrocyte by the malaria parasite Plasmodium falciparum, there appear in the erythrocyte membrane ‘new permeability pathways’ which mediate an increased permeability of the infected cell to a range of low molecular weight solutes, including anions, cations, amino acids, polyols and nucleosides. There is evidence that the pathways have an important bi-functional role: firstly, that the new permeability pathways are required for the uptake of essential nutrients, and secondly, for the removal of metabolic wastes from the infected cells. Reported screening of 165 analogues of the new permeability pathways inhibitor furosemide, and the related compound bumetanide, for their effect on the malaria parasite-induced choline influx resulted in the identification of 13 effective compounds. Of these, 5 showed inhibitory activity in vitro against the parasite at a concentration of 10 μM. Analysis of the data on all the 165 compounds revealed some preliminary structure-activity relationships. Based on this preliminary structure-activity relationship data, compounds with specific diversity sites were designed for synthesis. Acetolactate synthase (also known as acetohydroxyacid synthase) is the enzyme which catalyzes the first step in the biosynthesis of branched chain amino acids, including valine, leucine and isoleucine. It is a target for several classes of herbicides including sulfonyl ureas and imidazolinones. The complete crystal structure of yeast acetolactate synthase has been shown to share 26% homology with the Mycobacterium tuberculosis enzyme. On this basis, docking studies were initiated, which resulted in the generation of a virtual library of biaryl-based sulfonyl ureas. Exploratory libraries of sulfonyl ureas, imidazolinones, sulfonylcyanoguanidines, acylthioureas and related compounds (phthalimides) with the potential of having antituberculosis activity, presumably targeting acetolactate synthase, were synthesized. Studying the general approaches to the synthesis of sulfonyl ureas, the general procedure is to either react a sulfonamide with an isocyanate in the presence of a weak base, or to react a sulfonyl isocyanate with a primary or secondary amine. Both approaches work well chemically. However, the lack of diverse commercially available (sulfonyl) isocyanates, as well as the instability of isocyanates in general are drawbacks. A method that generates a vast selection of (sulfonyl) isocyanates from a range of commercially available starting materials would, hence, be very useful. A new approach to the synthesis of sulfonyl ureas was envisaged. This strategy involves the use of 1,2,4-dithiazolidine-3,5-dione, which should provide an alternative route to the arylsulfonyl ureas. en_ZA
dc.language.iso eng en_ZA
dc.subject.other Chemistry en_ZA
dc.title Synthesis and structure-activity relationship studies of novel anti-infectives for cross screening in tuberculosis and malaria disease models en_ZA
dc.type Thesis / Dissertation en_ZA
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 en_ZA
dc.type.qualificationname PhD en_ZA
uct.type.filetype Text
uct.type.filetype Image


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