Aryloxyethyl Thiocyanates Are Potent Growth Inhibitors of Trypanosoma cruzi and Toxoplasma gondii.
As a part of our project aimed at searching for new safe chemotherapeutic agents against parasitic diseases, several compounds structurally related to the antiparasitic agent WC-9 (4-phenoxyphenoxyethyl thiocyanate), which were modified at the terminal phenyl ring, were designed, synthesized, and evaluated as growth inhibitors against Trypanosoma cruzi, the etiological agent of Chagas disease, and Toxoplasma gondii, the parasite responsible of toxoplasmosis. Most of the synthetic analogues exhibited similar antiparasitic activity and were slightly more potent than our lead WC-9. For example, two trifluoromethylated derivatives exhibited ED50 values of 10.0 and 9.2 μM against intracellular T. cruzi, whereas they showed potent action against tachyzoites of T. gondii (ED50 values of 1.6 and 1.9 μM against T. gondii). In addition, analogues of WC-9 in which the terminal aryl group is in the meta position with respect to the alkyl chain bearing the thiocyanate group showed potent inhibitory action against both T. cruzi and T. gondii at the very low micromolar range, which suggests that a para-phenyl substitution pattern is not necessary for biological activity.
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires (Argentina).
María N
MN
Chao
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires (Argentina).
Carolina Exeni
CE
Matiuzzi
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA, 30602 (USA).
Melissa
M
Storey
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA, 30602 (USA).
Catherine
C
Li
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires (Argentina).
Sergio H
SH
Szajnman
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA, 30602 (USA).
Roberto
R
Docampo
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA, 30602 (USA).
Silvia N J
SN
Moreno
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires (Argentina). jbr@qo.fcen.uba.ar.
Juan B
JB
Rodriguez
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D013861:Thiocyanates / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development; D014709:Vero Cells
D000981:Antiprotozoal Agents; D013861:Thiocyanates; C031760:thiocyanate
antiparasitic agents; biological activity; chemotherapeutic agents; inhibitors; structure-activity relationships