A dissertation submitted to the Faculty of Science
University of the Witwatersrand
Johannesburg,
in fulfilment of the requirements of the degree of Master of Science
14 February 2017. / Spirooxindoles are an important class of spirocycles in organic and medicinal chemistry. They are characterised by a spiro-ring fused with the oxindole scaffold and have a wide range of biological activity. We are particularly interested in spirooxindoles because of their antimalarial activity. Malaria is a major health problem in many parts of the world and the burden caused by the disease is still of great concern. In 2015 alone, an estimated 438 000 deaths due to malaria were reported across the world, with 90% of the deaths occurring in Africa. The increase in drug resistance to currently used antimalarial agents has rendered most of them ineffective, thereby contributing to the high mortality rates. As a result, there is a need for the development of new effective antimalarial agents. In the search for a new class of antimalarial chemotypes, cipargamin, introduced as NITD609 by norvatis in 2010 was synthesised. This compound is a novel synthetic antimalarial candidate, with an IC50 of ~1 nM against P. falciparum strains, including multi drug-resistant strains.
Previously in our laboratory, several spirooxindole derivatives were synthesised using an imino Diels-Alder reaction, also known as the Povarov reaction. Of all the compounds synthesised, only those derived from a para-substituted aniline displayed activity in the low micromolar range (~5μM) against P. falciparum in vitro. In this project, we aimed to further explore the antimalarial activity of these compounds by designing and synthesising ring-opened analogues. The analogues were successfully synthesised by a Grignard addition reaction using N-Boc protected arylimines as electrophiles. Despite several attempts, we were unable to remove the Boc-protecting group in the final step.
The second series of compounds we aimed to synthesise were ring closed analogues lacking one aromatic ring. The compounds were synthesised starting from an imine condensation reaction between benzyl protected isatin with para-substituted 2-allyanilines. The 2-allylanilines were prepared by subjecting N-allylanilines to an aza-Cope rearrangement. The arylimines prepared were then subjected to a nucleophilic Grignard addition reaction with commercially available vinylmagnesium bromide to yield the intermediate necessary for the ring closure step. Unfortunately, the nucleophilic
addition reaction was unsuccessful. The ring-closure step is very crucial during the synthetic route as it gives rise to the desired ring closed analogues via ring-closing metathesis. Although we were unable to reach the final step in the synthesis of ring-closed analogues, some progress was made in developing methodology for the synthesis of these analogues.
The synthesised ring-opened analogues were screened for antimalarial activity against P. falciparum in vitro. Six hit compounds were identified from the series of compounds tested with tert-butyl 3-(2,4-dichlorophenethyl)-2-oxo-3-(p-tolylamino)indoline-1-carboxylate 60 being the most active compound in the series with an IC50 value of 0.60 nM against the FCR 3 Strain. In general, compounds derived from p-toluidine displayed the most potent activity. / MT2017
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/22725 |
| Date | January 2017 |
| Creators | Butsi, Kamogelo Rosinah |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | Online resource (125 leaves), application/pdf |
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