Synthesis and biological evaluation of 4-Cyano-3-Methylisoquinolines and related isoquinoline analogues against plasmodium falciparum

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Molecular Sciences, College of Science, Health and Engineering, La Trobe University, Bundoora.

In 2015, according to the World Health Organisation, there were an estimated 212 million cases of malaria and some 429,000 of these people did not survive. In addition to the burden on human health, there is a significant cost to bear globally from malaria. Plasmodium falciparum is the species which causes the most severe malarial disease and is the leading cause of death in Africa. Unfortunately P. falciparum has shown resistance to antimalarial drugs, diminishing their therapeutic efficacy and presenting a major barrier to disease management. This dissertation reports the efficient synthesis of a series of isoquinoline derivatives and the study of their potential anti-malarial activities. Screening of these small molecules in a parasite cellular assay was undertaken on asexual blood stage parasites of P. falciparum 3D7 and chloroquine-resistant W2mef strains using a colorimetric assay. The amount of parasite enzyme lactate dehydrogenase measured is positively correlated with parasite proliferation. In the first part of this project, a series of 1-substituted 3-methyl-4-cyanoisoquinolines were synthesised and derivatised at the 5- and 7-positions. The optimised synthetic route involved preparation of the isocarbostyril precursor followed by chlorination to give an intermediate which was immediately coupled with a variety of amines to produce substituted isoquinoline analogues. Several inhibitors were found to have EC50 values in the low micromolar range. The second part of the project involved the synthesis of cyclised isoquinolines using tin chloride dihydrate and sodium borohydride. A variety of isoquinolines were prepared which were functionalised at the 5-position. Biological evaluation showed submicromo lar EC50 values for the majority of the cyclised compounds. These encouraging results suggest these structures may be candidates suitable for consideration as new therapeutics for the treatment of malaria.