Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii

MARÍA N. CHAO; CATHERINA LI; MELISSA STOREY; BRUNO N. FALCONE; SERGIO H. SZAJNMAN; SERGIO M. BONESI; ROBERTO DOCAMPO; SILVIA N. J. MORENO; JUAN B. RODRIGUEZ

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2016 vol. 11 p. 2690 - 2702

1860-7179

Two obligate intracellular parasites, Trypanosoma cruzi, theagent of Chagas disease, and Toxoplasma gondii, an agent oftoxoplasmosis, upregulate the mevalonate pathway of theirhost cells upon infection, which suggests that this host pathwaycould be a potential drug target. In this work, a numberof compounds structurally related to WC-9 (4-phenoxyphenoxyethylthiocyanate), a known squalene synthase inhibitor, weredesigned, synthesized, and evaluated for their effect on T. cruziand T. gondii growth in tissue culture cells. Two fluorine-containingderivatives, the 3-(3-fluorophenoxy)- and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates, exhibited half-maximal effectiveconcentration (EC50) values of 1.6 and 4.9 mm, respectively,against tachyzoites of T. gondii, whereas they showedsimilar potency to WC-9 against intracellular T. cruzi (EC50values of 5.4 and 5.7 mm, respectively). In addition, 2-[3-(phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which isa hybrid inhibitor containing 3-phenoxyphenoxy and bisphosphonategroups, has activity against T. gondii proliferationat sub-micromolar levels (EC50=0.7 mm), which suggests a combinedinhibitory effect of the two functional groups.