Synthesis and Evaluation of Polyamines as Antimalarial Agents

Plasmodium species is transmitted between humans by the female anopheles mosquito. It kills 1.5-2.7 million people every year and 40% of humanity lives in an endemic area. Throughout time numerous attempts have been made to control the disease through natural remedies such as quinine (A) and artemisinin (B), synthetic drugs e.g. chloroquine (C), and also by the use of bed nets and insect repellents. Polyamines such as putrescine (D), spermidine (E) and spermine (F) are naturally occurring and are widespread in nature. They have been shown to be important in fundamental processes such as cell proliferation and differentiation. The study of these compounds has led to the development of polyamine analogues to treat a wide range of diseases from cancer and parasitic diseases through to their use as anti-fungal agents. We started work in this area when a simple putrescine analogue (G) was shown to have promising antimalarial activity and became the "lead" compound for this project. Initially we synthesized a number of analogues of (G) varying the carbon chain and the substitution patterns on the nitrogens. We did not see any improvement in activity until a N,N'-bisbenzyl compound was prepared; however in vivo results were disappointing. We decided to investigate analogues of higher polyamines as these had shown better activity than putrescine analogues by workers in the cancer field. Surprisingly the spermidine analogues that were prepared showed little antimalarial activity, although separate tests showed them to have excellent anti-fungal properties. The spermine analogues synthesized were more promising with the bisbenzyl analogue (H) the most active in vitro so far. It was known that the genome of P. falciparum is rich in adenine and thymine base pairs compared to the human host so we decided to study some AT specific binding agents to see if this improved the activity. We decided to incorporate the N,N-dimethylaminoethyl (I) and propioamidino (J) moieties into spermine analogues to see if antimalarial activity increased. These functional groups had been used previously in AT binding agents. No test data is available on these compounds. A number of compounds were prepared and we observed increased activity as we added hydrophobic benzyl groups and also as we increased the number of nitrogens present to four, as in spermine analogues. This is in agreement with the hypothesis that DNA binding is related to the activity of the compounds which itself is controlled by the increased number of nitrogens in the compound. A number of compounds are still awaiting testing. We have prepared a range of polyamines, both known and novel, and examined their antimalarial activity