Synthesis and modification of antiplasmodial antifolates

Abstract

There are many diseases responsible for the countless deaths in the African continent, one of which is malaria. Malaria is an ancient parasitic disease caused by the parasite of the genus Plasmodium, which is widely transmitted by the anopheles mosquito. This disease has been reported to have claimed millions of lives across the world and urgent solutions have been sought after since the epidemic. In attempts to manage the disease, the anti-malaria community has introduced management approaches which span the scope of environmental control and pest management. Of great importance of these approaches has been the chemotherapeutic approach towards combating the disease. The main issue associated with the chemotherapy approach has been the rise of drug resistance. Considering this drug resistance, ways to salvage the available drug knowledge, methods such as combination therapy have risen and have proven effective to a certain extent. Nonetheless, the journey towards developing drugs which could potentially eradicate malaria continues. In this two-part project we sought to synthesize compounds which could potentially exhibit DHFR inhibitory properties. The first part of the project consists of the synthesis of flexible pyrimidine analogues from a 3-step synthetic route. This route began with a multicomponent reaction starting with commercially available aldehydes, malononitrile and guanidine hydrochloride to yield a 6-substituted 2,4-diaminopyrimidine carbonitrile. This precursor was further functionalized at the nitrile 5-position by means of a hydrogenation reaction to give an aldehyde. This aldehyde was then coupled to a commercially available phenethylamine by means of a reductive amination reaction to give the desired flexible pyrimidine analogue. Despite successfully completing the synthetic steps, the compounds were difficult to work with and thus we encountered an issue with the purity of the target compounds since purification by conventional methods was not viable. In the second part of the project we sought to access compounds with a scaffold like the one envisioned in the first part of the project via accessing a rigid intermediate. We accessed the rigid compounds via a coupling reaction between two acetylenes. The library of ten analogues was successfully synthesized and was taken for testing and due to time constraints; we were unable to establish their activity in a whole cell P. falciparum assay. One of these rigid intermediates with the butyne linker was then reduced using a hydrogenation reaction conditions to give the flexible analogue.