Investigation of herbicide-based compounds as novel anti-malarial agents

Abstract

Plasmodium falciparum causes the most severe form of malaria in humans. Currently, no effective vaccine exists and the emergence of widespread drug resistance in the parasite has further increased the necessity for novel therapeutics to be discovered. Microtubules are cytoskeletal polymers which consist mainly of repeating a/β- tubulin heterodimers and play crucial roles in almost all eukaryotic cells. These polymers have the ability to rapidly elongate and shorten. Inhibition of this dynamic behaviour has been successftilly exploited in the past to generate potent fungicides, herbicides, anti-parasitics and anti-cancer therapeutics. For Plasmodium, two groups of chemically distinct herbicides, the dinitroanilines and the phosphorothioamidates, were previously identified as being potentially useful antimalarial agents. To improve the activity of these herbicides for Plasmodium, a library of amiprophosmethyl- related compounds were generated by collaborators in the Royal College of Surgeons in Ireland. The major objective of this project was to investigate the cellular and molecular interactions of these compounds with the Plasmodium tubulin.