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

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

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

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

1860-7179

Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host path- way could be a potential drug target. In this work, a number of compounds structurally related to WC-9 (4-phenoxyphenox- yethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells. Two fluorine-con- taining derivatives, the 3-(3-fluorophenoxy)- and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates, exhibited half-maximal ef- fective concentration (EC50) values of 1.6 and 4.9 mm, respec- tively, against tachyzoites of T. gondii, whereas they showed similar potency to WC-9 against intracellular T.cruzi (EC50 values of 5.4 and 5.7mm, respectively). In addition, 2-[3- (phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which is a hybrid inhibitor containing 3-phenoxyphenoxy and bis- phosphonate groups, has activity against T. gondii proliferation at sub-micromolar levels (EC50 = 0.7 mm), which suggests a com- bined inhibitory effect of the two functional groups.