In recent years investigation of the biological mode of action of the antimalarial compound atovaquone has validated the Plasmodium falciparum bC1 protein complex as a target for the development of novel antimalarials. This project is concerned with the design, synthesis and development of quinolone based antimalarial compounds targeting the Qo site of the Plasmodium falciparum bC1 protein complex. -......, ..•. : - A small array of quinolone-based compounds, substituted at the 3 and 7 positions, has been developed utilising the Gould-Jacobs methodology. The synthesised compounds express activity as low as 0.46 nM versus Plasmodium falciparum malaria parasites in vitro. Activity at the bC1 protein complex has been confirmed and selectivity for the parasite protein over the mammalian equivalent has been demonstrated. Poor solubility has been highlighted as a potential issue; however steps have been taken towards the ,/ development of carbamate prod rugs with encouraging results. Docking studies performed in silico, using the crystallised structure of yeast bC1 protein, demonstrate a key role for residues His181 and Glu272 in the recognition of high potency inhibitors and have aided in the rationalisation of the observed biological activities. The orientation of the quinolone group in the active site and interaction of the inhibitors with the hydrophobic channel leading to the active site have both been shown to be of significance for biological potency. Computer lead design of a new chemotype has resulted in the development of a second array of quinolone based compounds synthesised by a divergent method based on the Huisqen 1,3-dipolar cycloaddition. Docking studies predicted the synthesised compounds to be potent inhibitors of Plasmodium falciparum bC1. However, in vitro results for the array proved disappointing, an outcome attributed to a failure to account for membrane permeability and the physical location of the targeted bC1 protein complex.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:569047 |
| Date | January 2012 |
| Creators | Cowley, Robin Neil |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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