Coenzyme A biosynthesis inhibitors as potential anti-parasitic agents

Malaria is a lethal disease responsible for human deaths numbering hundreds of thousands every year. With increasing resistance to most antimalarial drugs, new approaches are of high importance. Coenzyme A (CoA) plays a key role in the biosynthesis of many important compounds and is synthesised from pantothenic acid (Vitamin B5) via a series of five enzyme-mediated steps. Studies have shown that the human malaria parasite P. falciparum is unable to synthesise pantothenic acid, and is therefore dependent on uptake from its environment. CJ-15,801, a naturally occurring pantothenic acid analogue that differs only in the incorporation of a very reactive enamide unit at its core, was isolated in 2001. CJ-15,801 has shown remarkable specificity for inhibiting P. falciparum growth over mammalian cell lines. The enantioselective synthesis of CJ-15,801 from (D)-pantolactone has been achieved along with a library of over 100 related enamide analogues. Biological evaluation of the enamides against P. falciparum has uncovered promising leads, with single figure micromolar level antiplasmodial activity as well as nanomolar activity in pantothenate phosphorylation assays. In an effort to understand the mode of action of the enamide analogues, multiple approaches have been taken. Activity against P. falciparum was assessed in such a way that pantothenate competitive and non-competitive inhibitors could be identified. Additionally, 13C-labelled analogues have been synthesised for metabolomic studies and fluorescently tagged compounds based on the BODIPY scaffold have been synthesised for evaluation using fluorescence microscopy