Anti-cancer and anti-malarial 4-aminoquinoline derivatives : synthesis and solid-state investigations

Master Thesis


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University of Cape Town

The work presented in this thesis is two-fold: (i) development of single agents that provide inhibition of both the growth of malaria parasites and of tumour cells in vitro, and (ii) inclusion of these potential novel inhibitors in cyclodextrin host molecules in an attempt to render these dual drugs water-soluble. Of all the current clinically established antimalarials, the 4-aminoquinolines haveproven to be the most significant and efficacious for the treatment and prophylaxis of malaria. However, their efficacy has decreased by the spread of drug resistant strains of the causative agent Plasmodium Jalciparum. Future research into 4-aminoquinoline derivatives as antimalarial agents is still warranted and justified on the basis of several considerations. The quinoline moiety has also been shown to be a substructure in multi-drug resistance reversal agents against certain cancer cell lines and antitumour agents which have demonstrated the ability to act as differentiation-inducing agents. The strategy employed for this project was to hybridize chalcone moieties and their Mannich base derivatives with the 4-aminoquinoline moiety. This dual drug concept uses the basic structure of the chalcone scaffold, which has a wide range of known antimalarial and anticancer activities, and is hybridised with the 4-aminoquinoline moiety, in order to exert maximal biological activity and overcome or prevent drug resistance. Structural variation on the aromatic rings of the chalcone scaffold allowed preliminary structure-activity relationship studies to be undertaken.

Includes bibliographical references.