Artículo

Chao, M.N.; Storey, M.; Li, C.; Rodríguez, M.G.; Di Salvo, F.; Szajnman, S.H.; Moreno, S.N.J.; Docampo, R.; Rodriguez, J.B. "Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation" (2017) Bioorganic and Medicinal Chemistry. 25(24):6435-6449
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Abstract:

The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084 µM, 0.11 µM, 0.083, µM, 0.085, and 0.075 µM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1800 making these molecules promising candidates as antiparasitic agents. © 2017 Elsevier Ltd

Registro:

Documento: Artículo
Título:Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation
Autor:Chao, M.N.; Storey, M.; Li, C.; Rodríguez, M.G.; Di Salvo, F.; Szajnman, S.H.; Moreno, S.N.J.; Docampo, R.; Rodriguez, J.B.
Filiación:Departamento de Química Orgánica and UMYMFOR (CONICET–FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, Buenos Aires, C1428EHA, Argentina
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, United States
Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Buenos Aires, C1428EGA, Argentina
Palabras clave:2,4 dichlorophenoxyethyl selenocyanate; 3 (2 fluorophenoxy)phenoxyethyl selenocyanate; 3 (3 fluorophenoxy)phenoxyethyl selenocyanate; 3 (3 pyridyl)oxyphenoxyethyl selenocyanate; 3 (4 chlorophenoxy)phenoxyethyl selenocyanate; 3 (4 fluorphenoxy)phenoxyethyl selenocyanate; 3 (phenylthio)phenoxyethyl thiocyanate; 3 iodophenoxyethyl selenocyanate; 3 phenoxyphenoxyethyl selenocyanate; 4 (3 fluorophenoxy)phenoxyethyl selenocyanate; 4 (4 fluorophenoxy)phenoxyethyl selenocyanate; 4 (phenylthio)phenoxyethyl thiocyanate; 4 iodophenoxyethyl selenocyanate; 4 phenoxy 2 (selenocyanatomethyl) 2,3 dihydrobenzofuran; 4 phenoxyphenoxyethyl carbamate; 4 phenoxyphenoxyethyl cyanate; 4 phenoxyphenoxyethyl selenocyanate; 4 phenoxyphenoxyethyl thiocyanate derivative; 5 phenoxy 2 (selenocyanatomethyl) 2,3 dihydrobenzofuran; 5 phenoxy 2 (thiocyanatomethyl) 2,3 dihydrobenzofuran; 5 phenoxy 2 (thiocyanatomethyl)benzofuran; 6 phenoxy 2 (selenocyanatomethyl) 2,3 dihydrobenzofuran; benznidazole; selenium; squalene synthase inhibitor; unclassified drug; 4-phenoxyphenoxyethyl thiocyanate; antitrypanosomal agent; diphenyl ether derivative; selenium; thiocyanic acid derivative; antiprotozoal activity; Article; controlled study; drug design; drug effect; drug screening; drug structure; drug synthesis; ED50; growth inhibition; nonhuman; tissue culture cell; Trypanosoma cruzi; animal; cell proliferation; cell survival; chemical structure; chemistry; Chlorocebus aethiops; cytology; dose response; drug effects; drug sensitivity; growth, development and aging; structure activity relation; synthesis; Trypanosoma cruzi; Vero cell line; Animals; Cell Proliferation; Cell Survival; Cercopithecus aethiops; Dose-Response Relationship, Drug; Molecular Structure; Parasitic Sensitivity Tests; Phenyl Ethers; Selenium; Structure-Activity Relationship; Thiocyanates; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells
Año:2017
Volumen:25
Número:24
Página de inicio:6435
Página de fin:6449
DOI: http://dx.doi.org/10.1016/j.bmc.2017.10.016
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:benznidazole, 22994-85-0; selenium, 7782-49-2; 4-phenoxyphenoxyethyl thiocyanate; Phenyl Ethers; Selenium; Thiocyanates; Trypanocidal Agents
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v25_n24_p6435_Chao

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Citas:

---------- APA ----------
Chao, M.N., Storey, M., Li, C., Rodríguez, M.G., Di Salvo, F., Szajnman, S.H., Moreno, S.N.J.,..., Rodriguez, J.B. (2017) . Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation. Bioorganic and Medicinal Chemistry, 25(24), 6435-6449.
http://dx.doi.org/10.1016/j.bmc.2017.10.016
---------- CHICAGO ----------
Chao, M.N., Storey, M., Li, C., Rodríguez, M.G., Di Salvo, F., Szajnman, S.H., et al. "Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation" . Bioorganic and Medicinal Chemistry 25, no. 24 (2017) : 6435-6449.
http://dx.doi.org/10.1016/j.bmc.2017.10.016
---------- MLA ----------
Chao, M.N., Storey, M., Li, C., Rodríguez, M.G., Di Salvo, F., Szajnman, S.H., et al. "Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation" . Bioorganic and Medicinal Chemistry, vol. 25, no. 24, 2017, pp. 6435-6449.
http://dx.doi.org/10.1016/j.bmc.2017.10.016
---------- VANCOUVER ----------
Chao, M.N., Storey, M., Li, C., Rodríguez, M.G., Di Salvo, F., Szajnman, S.H., et al. Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation. Bioorg. Med. Chem. 2017;25(24):6435-6449.
http://dx.doi.org/10.1016/j.bmc.2017.10.016