The synthesis and biological evaluation of novel analogues of isocryptolepine

Abstract

This thesis investigates the potential of the alkaloid isocryptolepine 16 as a lead compound in antimalarial drug development. Fifteen derivatives of the parent alkaloid were prepared and fully characterised, twelve of which were novel compounds. A select group of compounds were subsequently evaluated for both antimalarial activity and cytotoxicity.Three previously reported synthetic methodologies to the parent alkaloid were initially investigated; wherein two approaches were able to be reproduced or improved. These two synthetic methodologies were subsequently applied to the preparation of derivatives. The first of these methodologies, the Jonckers Method, involved two consecutive palladium catalysed coupling reactions. During the course of these investigations it was found that these two reactions could be combined into a single ‘domino’ reaction resulting in a reduction in the number of steps required to prepare the parent alkaloid. This methodology was then applied to the preparation of both ring-substituted and structural isomers. The second methodology, The Molina Method, involved a benzotriazole-mediated strategy and was applicable to preparing isocryptolepine derivatives with ring substituents on the quinoline ring. Finally a method for selective electrophilic aromatic substitution was developed and applied to the preparation of a further range of halogenated derivatives.Eight of the prepared derivatives were selected for biological evaluation. Antimalarial activity was assessed against a chloroquine sensitive and resistant strain of P. falciparum, whilst cytotoxicity was evaluated against mouse embryonic fibroblasts (3T3 cells). All compounds were found to be more active compared to the parent alkaloid against the chloroquine resistant strain of P. falciparum; specifically 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 85 nM) and 8-bromo-3-chloroisocryptolepine 105 (IC[subscript]50 = 100 nM) were the most potent. Cytotoxicity evaluations revealed that ring substitution did not enhance cytotoxicity and the most potent antimalarial derivative, 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 9.01 μM), displayed a 4-fold reduction in cytotoxicity.In conclusion, isocryptolepine 16 and its derivatives have significant potential as antimalarial lead compounds, with many derivatives possessing enhanced bioactivity versus the parent. This study has also identified 8-bromo-2-chloroisocryptolepine 107 to be a very promising lead compound which warrants further biological or pharmaceutical investigation.