Lang'at, Caroline Chelang'at; (1995) Synthesis and biological activities of quassinoid analogues. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Malaria affects more than 300 million people and is responsible for the death of over one million children annually. The spread of strains of the malaria parasites, particularly P. falciparum, which are resistant to clinically used antimalarial drugs such as chloroquine has intensified the search for alternative natural product based or synthetic drugs with novel modes of action. Plants from the Simaroubaceae family are used in traditional medicine to treat malaria and their biological activity is attributed to the quassinoids which they contain. In this study, two approaches have been made towards the production of synthetic quassinoids. Firstly, naturally occurring and commercially available quassin, which is inactive against P. falciparum in vitro has been chemically modified and a series of derivatives prepared. Semisynthetic analogues of brusatol and bruceine A, two potent antimalarial quassinoids, have been prepared. Secondly, the total synthesis of bicyclic and tricyclic analogues of quassinoids starting from 2-methylcyclohexanone. Some 115 compounds have been prepared and 105 tested for antimalarial activity against the multidrug resistant strain of P. falciparum in vitro. Chemically modifying quassin has yielded novel compounds with enhanced in vitro antimalarial activity. An investigation into the possible mode of action revealed that quassin and brusatol analogues inhibit protein synthesis more rapidly than nucleic acid synthesis in P. falciparum, while the bicyclic and tricyclic analogues do not have this apparent selectivity of action. Selected compounds have been assessed for their toxicity against brine shrimp in a lethality test, their cytotoxicity against KB cells in vitro and a comparison made with their in vitro antimalarial activities. Some compounds are more selective for the malaria parasite. The insecticidal activity of a number of quassinoid analogues against the mustard beetle, housefly and plutella larva has also been investigated.

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