Activity of fluorine?containing analogues of WC-9 and structurally related analogues against two intracellular parasites: Trypanosoma cruzi and Toxoplasma gondii.

CHAO, MARÍA NOELIA; LI, CATHERINE; STOREY, MELISSA; FALCONE, BRUNO NICOLÁS; SZAJNMAN, SERGIO HERNÁN; BONESI, SERGIO MAURICIO; DOCAMPO, ROBERTO; MORENO, SILVIA N.; RODRIGUEZ, JUAN BAUTISTA

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2016

1860-7179

Two obligate intracellular parasites, Trypanosoma cruzi, agent of Chagas disease, and Toxoplasma gondii, agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, suggesting that this host pathway could be a potential drug target. In this work we designed, synthesized and evaluated the effect of a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi and T. gondii growth in tissue culture cells. The fluorine-containing derivatives 3-(3-fluorophenoxy) and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates exhibited EC50 values of 1.6 µM and 4.9 µM, respectively, against tachyzoites of T. gondii, while they showed similar potency as WC-9 against intracellular T. cruzi (EC50 values 5.4 µM and 5.7 µM, respectively). In addition, 2-[3-(phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which is a hybrid inhibitor containing 3-phenoxyphenoxy and bisphosphonate groups, has activity on T. gondii proliferation at sub micromolar levels (EC50 = 0.7 µM), suggesting combined inhibitory effect of the two functional groups.