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Small molecule inhibitors of parasitic enzymes

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dc.contributor.advisor Chilabe K, Prof en
dc.contributor.author Chipeleme A en
dc.date.accessioned 2016-09-22T09:11:40Z
dc.date.available 2016-09-22T09:11:40Z
dc.date.submitted 2005 en
dc.identifier.uri http://hdl.handle.net/20.500.11892/46458
dc.description.abstract The work presented in this thesis is threefold:-(i) development of potential novel inhibitors of cysteine proteases from the causative agents of Malaria, African sleeping sickness and Chagas disease, (ii) development of potential new and novel antitrypanosomal inhibitors of trypanosome alternative oxidase, and (iii) synthetic and methodological studies. The emergence of the widespread resistance of Plasmodium falciparum to the available drugs has necessitated the search for new lead compounds with high structural variation. Among potential novel targets for antimalarial chemotherapy are enzymes such as cysteine proteases that mediate hemoglobin hydrolysis. The design, synthesis and biological evaluation of four different classes of Mannich bases as potential new inhibitors of a cysteine protease (falcipain-2) from P.falciparum was undertaken. Biological screens were also extended to two other important homologous parasitic trypanosomal cysteine proteases, cruzain and rhodesain. From the assays two compounds 83b and 83c from the series of 4-aminoquinoline semicarbazones were identified as promising antiparasitic agents against all the three cysteine proteases, and one compound 91a from the series of Mannich bases of semicabazones of isatin derivatives against chloroquine sensitive (D10) and chloroquine resistant (K1) strains of the malaria parasite. Trypanosome alternative oxidase (TAO) is a terminal oxidase present in the bloodstream form of African trypanosomes which are responsible for human African sleeping sickness and nagana in cattle. TAO is present in the mitochondria of the trypanosomes and is an additional (in addition to cytochrome c oxidase) protein in the respiratory chain. TAO acts as the terminal electron acceptor and its substrates are ubiquinol and dioxygen which are converted to ubiquinone and water respectively. Based on the hypothesis that salicylhydroxamic acid (SHAM) and related compounds inhibit TAO by interfering with ubiquinone, a series of prenylated amides, which closely resemble ubiquinone, were designed, synthesized and tested against the enzyme. Biological data showed that these compounds have comparable inhibitory activity to SHAM at high concentrations and that they act by interfering with ubiquinone/ubiquinol mediated electron transport, more specifically by binding to the terminal ubiquinol receptor on the oxidase component of the TAO. (iii) Investigations into the copper (I)-catalyzed homologation of alkynes to give allenes via Mannich bases revealed that product (allene vs homocoupling product) and yield distribution are dependent upon the nature of the anionic component of the copper catalyst and the electronic nature of a substituent on the aryl ring of an alkyne substrate. When a copper catalyst with a non-linear anionic component was employed, no allene products were obtained. On the other hand, the yields of homocoupling products decreased as the strength of the electron withdrawing group on the aryl ring increased. Operationally simplified and high yielding methods for the preparation of N, N'- bis(benzyloxycarbonyl)-1-L-cysteinyl-glycyl-3-dimethylaminop an alternative substrate for trypanothione reductase, and structural analogues, using polymer-supported reagents are described. Solid phase synthesis of a biaryl chalcone is also described. en
dc.language English en
dc.subject Chemistry en
dc.title Small molecule inhibitors of parasitic enzymes en
dc.type Doctoral degree en
dc.description.degree PhD en


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