M.Sc. (Chemistry) / The objective of the project was the synthesis of thiosemicarbazone-triazole hybrid compounds and evaluation of their biological activities against malaria and obesity. In achieving our objective, compound 63 was synthesized from the reaction of benzaldehyde 62 with propargyl bromide. Click chemistry reaction of compound 63 with benzyl azide provided triazole 68. Schiff’s base condensation of triazole 68 with methyl hydrazine carbodithioate 67 furnished compound 69 which then underwent nucleophilic substitution reaction and afforded thiosemicarbazone-triazole hybrids 61a-j. The structures of the compounds were characterized using NMR spectroscopy and elemental analysis. Hybrids 61a-h were then investigated for their biological activities against malaria and obesity. The antimalarial activities of the hybrids against the 3D7 strain of the malaria parasite plasmodium falciparum showed that only hybrid 61f exhibited less than 50% parasite viability (46% compared to 37% of chloroquine). The dose response of the hybrids was not carried out due to their poor activities. Hybrids 70a-h that incorporated electron donating group in their aromatic linker were synthesized similarly as hybrids 61a-h were synthesized. Their antimalarial activities showed that all except 70c and 70g exhibited less than 50% parasite viability. The test results indicated that the addition of methoxy group to the hybrids 61b, 61e and 61f decreased their percentage parasite viability which were exhibited by their corresponding hybrids 70b, 70e and 70f, respectively. Hybrid 70f was found to be marginally active with a dose response of 7.09 μM. The anti-obesity and anti-diabetic effects of hybrids 61a-h were investigated against the mitochondrial genes (Acc-1, Cpt-1 and Pgc-1) and glucose transport genes (Glut-4, Mef2a and Nrf-1), respectively. The test results against the mitochondrial genes showed that hybrids 61e and 61h consistently exhibited on the 3 genes which indicated that the presence of a non-polar short branched chain of the amine moiety might be important in the up-regulation of oxidative (Cpt-1 and Pgc-1) and down regulation of lipid accumulation (Acc-1) genes. The test results on the glucose transport genes showed that 61e followed by 61f consistently exhibited on the 3 genes which indicated that the presence of a non-polar short branched chain of the amine moiety might be important in the up-regulation of Glut-4, Mef2a and Nrf-1.Hybrids 70a-h were also tested against obesity and type 2 diabetes mellitus. Their investigation on the mitochondrial genes showed that the addition of methoxy group to the hybrids 61a-h that have a non-polar long branched chain of the amine moiety could be a reason for the expression and suppression of Cpt-1, Pgc-1 and Acc-1, respectively. The test results of hybrids 70a-h on glucose transport genes showed that the addition of methoxy group to the hybrids 61a-h that have a non-polar short (straight and branched) alkyl chain of the amine moiety might be a reason for the up-regulation of Glut-4, Mef2a and Nrf-1. Carbohydrate incorporated thiosemicarbazone-triazole hybrid compound 75 was successfully synthesized. However, the synthesis of more libraries of compound 75 and investigation of their biological activities against malaria and obesity were not carried out due to time constraints.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uj/uj:11601 |
| Date | 26 June 2014 |
| Creators | Belay, Yonas Habtegiorghies |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
| Rights | University of Johannesburg |
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