Browsing by Author "Jacobs, Leon"
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- ItemSynthesis and biological evaluation of novel ferroquine and phenylequine analogues(Stellenbosch : Stellenbosch University, 2013-03) Jacobs, Leon; Blackie, Margaret A. L.; De Villiers-Chen, Katherine; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.Please refer to full text to view abstract.
- ItemSynthesis of fused heterocyclic aromatic compounds as potential antiplasmodial agents(Stellenbosch : Stellenbosch University, 2017-12) Jacobs, Leon; Blackie, Margaret A. L.; Pelly, S. C.ENGLISH ABSTRACT: 3-Methyl benzofuran antiplasmodial compounds have been described in literature and and synthesis of heterocyclic derivatives forms the basis of this project. These benzofuran compounds were synthesized with the primary role as effective inhibitors of the enzyme Plasmodium falciparum N-Myristoyl transferase (PfNMT). PfNMT plays an important enzymatic function in the majority of all living organisms, facilitating the myristoylation of N-terminal glycine residues of proteins that serve many functions in vivo, and is considered vital to the viability of not only most organisms, but P. falciparum too. The rationale behind the key features of these antiplasmodial compounds include the heterocyclic scaffold that induces π – π stacking with amino acid residues at the active site of PfNMT, aromatic amide and ester groups also necessary for π – π stacking and a piperidinium salt coupled to the heterocycle, providing a salt-bridge interaction with neighboring amino acid residues. Five different heterocycles were synthesized with the primary function of replacing the benzofuran moiety in order to ascertain which heterocyclic system is the most efficacious. We synthesized indole, 3-methyl indole, 1-methyl benzimidazole, benzoxazole and benzothiophene scaffolds, each containing an ester group at the C2-position necessary for transesterification and amidation reactions, as well as a phenolic group at the C4-position (C7-position for the benzimidazole scaffold) required for the introduction of a piperidine group. The Boc-protected piperidine group was introduced first, followed by esterification reactions with 2-phenylethanol, benzyl alcohol and 1-naphthalenemethanol. Amidation reactions were also carried out with 2-phenethylamine, benzylamine, 1-naphthylmethylamine and 4-(aminomethyl)pyridine. The synthesis of each series of heterocyclic antiplasmodials was realized after the final Boc-deprotection step, providing all the compounds in salt form. These compounds were sent for whole-cell testing against a P. falciparum chloroquine sensitive strain (NF54) with the intention to prove which heterocycle and aromatic ester or amide substituent improves the efficacy the most, and validate the importance of a methyl group on the 3-methyl indole and 1-methyl benzimidazole scaffold when comparing the efficacy of analogous esters and amides. The results indicated that the benzoxazole series of compounds were inactive and the 3-methyl indole series are the most active which returned IC50 values of 0.56 – 6.1 μM respectively, but is trailed closely in efficacy by the indole (IC50 values of 0.83 – 6.5 μM) and benzothiophene (IC50 values of 0.71 – 5.9 μM) series of compounds. The 1-methyl benzimidazole series of compounds were the least active with IC50 values between 7.4 – 13.3 μM apart from one compound indicating an IC50 value of 1.1 μM.