WC-9 a Lead Drug with Great Prospects for American Trypanosomiasis and Toxoplasmosis

Abstract

Trypanosomatids have a strict demand for specific endogenous sterols for survival and cannot use the abundant supply of cholesterol present in their mammalian hosts. Depletion of endogenous sterols such as ergosterol or of its next biosynthetic product 24-ethylcholesta-5,7,22-trien-3ß-ol elicits a growth inhibition effect on Trypanosoma cruzi, the etiologic agent of American trypanosomiasis or Chagas disease. These metabolites cannot be replaced by cholesterol; consequently, the enzymes implicated in catalyzing their formation constitute interesting molecular targets for drug design. Selective inhibition of a crucial enzyme associated to the ergosterol biosynthetic pathway in the parasite will arrest T. cruzi proliferation. Trypanosomatids such as T. cruzi as well as fungi and yeasts require these specific endogenous sterols for cell viability and growth. For these reasons, ergosterol biosynthesis inhibitors with potent in vitro activity and appropriate pharmacokinetic properties in mammals have become putative antiparasitic agents by inducing radical parasitological cure in animal models of both acute and chronic experimental Chagas disease. WC-9 (compound 1; 4-phenoxyphenoxyethyl thiocyanate) holds our attention bearing in mind that this compound exhibits IC50 values at the low nanomolar range against the clinically more relevant replicative form of T. cruzi (amastigotes). The growth inhibitory effects of WC-9 are associated with a depletion of the parasite endogenous sterols, ergosterol and its 24-ethyl analogue, indicating a blockade of the biosynthetic pathway at a pre-squalene level.