- Title
- Investigation of α-aryl substituted 3-indolylethanones as potential antiplasmodial agents
- Creator
- Svogie, Archibald Lesley
- Date Issued
- 2016
- Date
- 2016
- Type
- text
- Type
- Thesis
- Type
- Masters
- Type
- MPharm
- Identifier
- http://hdl.handle.net/10962/55487
- Identifier
- vital:26704
- Description
- According to the World Health Organisation (WHO), deaths attributed to Plasmodium falciparum exceeded 584 000 in 2013, with 198 million new cases of malaria being reported. One contributing factor to these alarming figures is the emergence of drug resistance against available antimalarial agents. Therefore, there is a pressing need to develop new therapeutic antimalarial drugs with novel mechanisms of action in order to curb the increasing spread of malaria. The indole scaffold is often associated with biologically active compounds, recently exemplified by the antimalarial agent NITD609, which is currently in phase 1 clinical trials. Based on the biological evaluation of a small series of indolyl-3-amides and esters which showed moderate antimalarial activity, coupled to significant toxicity, we were prompted to investigate the synthesis of a series of indolyl-3-ethanone-α-amines (3.37 and 3.41), ethers (3.39 and 3.44) and thioethers (3.42, 3.43, 3.40, 3.45 – 3.73), where the carbonyl moiety and respective heteroatom were separated by a methine spacer. We further investigated these compounds for in vitro biological activity against P. falciparum and a human HeLa cell line. Our study explored the synthetic pathway of a three-step procedure toward our target compounds, with the initial Friedel-Crafts acetylation of indole, followed by α-bromination of the respective 3-acetylindoles. Finally, the halogen of the α-bromo ketone was substituted with an appropriate nucleophile, to yield our desired compounds. Various reagents were explored to optimise the nucleophilic displacement step, including potassium carbonate and various silver containing compounds. While many of the silver salts were found to assist in nucleophilic substitution, none were superior to the addition of potassium carbonate. The majority of compounds, chiefly the thioethers, displayed promising antimalarial activity, against the chloroquine sensitive 3D7 P. falciparum strain, with two thioethers in particular (3.54 and 3.65) inhibiting P. falciparum in the low nanomolar range. Additionally, active compounds were generally found to be non-toxic against HeLa cells, indicating that indolyl-3-thioethers are selective for the malaria parasite. These findings allowed us to begin hypothesising a structure activity relationship of this class, as well as elucidating the possible pharmacophore. In a speculative attempt to uncover the possible mechanism of action of these active compounds, in silico docking studies were conducted against Staphylococcus aureus HPPK (PDB ID: 4CRJ), which is an enzyme that immediately precedes DHPS in the microbial folate biosynthesis. Inhibition of folate biosynthesis is a validated selective antimalarial pathway and HPPK also exists in P. falciparum. Results from these docking studies suggested that our inhibitors bound well in the HPPK ATP pocket and were supportive of our hypothesized structure activity relationship.
- Format
- 108 leaves
- Format
- Publisher
- Rhodes University
- Publisher
- Faculty of Pharmacy, Pharmacy
- Language
- English
- Rights
- Svogie, Archibald Lesley
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