Allen, David; (1994) Antiprotozoal activities of quassinoids. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Quassinoids are degraded triterpenes found in species of the plant family Simaroubaceae. Many have been shown to have antiprotozoal activity both in vitro and in vivo. In the first part of this study, the development and validation of a simple method for testing drug combinations in vitro is described. Antagonism is demonstrated between the quassinoid bruceantin and, the known protein synthesis inhibitor, emetine when tested against three types of protozoa (Plasmodium falciparum. Entamoeba histolytica and Giardia intestinalis) and a human tumour cell line. Further studies involving the combination of both quassinoid and non- quassinoid drugs are described and discussed. The effects of a herbal tea, produced from Brucea javanica fruits, and, a component quassinoid, brusatol upon protein synthesis and nucleic acid synthesis in P. falciparum are shown to parallel one another. Data is shown which suggests that the effects observed for brusatol, against P. falciparum, are reversible. The synthesis of eight ester or ether derivatives of brusatol and a lipophylic ester of quassin is described. The associated in vitro antimalarial potency and KB cell cytotoxicity data of these compounds is presented- C3 acylation of brusatol with either a lipidic α-amino acid or acetic acid produced a compound of equivalent antimalarial activity, when compared with the parent quassinoid, but with reduced KB cell toxicity. The C3 and C15 esters of brusatol or bruceine A have been shown to be unaffected by various mammalian esterases. Quantitative structure-activity relationships for 42 quassinoids against P. falciparum, 21 against human KB cells and 17 against Entamoeba histolytica have been determined and the findings discussed. The requirements for antimalarial selectivity have also been calculated. The cellular protein content of P. falciparum (trophozoites), E. histolytica and human KB cells have been determined and used to standardise the in vitro antimalarial, antiamoebic and KB cell cytotoxicity activities respectively.

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