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Abstract:

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 pathway could be a potential drug target. In this work, a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl 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-containing derivatives, the 3-(3-fluorophenoxy)- and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates, exhibited half-maximal effective concentration (EC50) values of 1.6 and 4.9 μm, respectively, against tachyzoites of T. gondii, whereas they showed similar potency to WC-9 against intracellular T. cruzi (EC50values of 5.4 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 against T. gondii proliferation at sub-micromolar levels (EC50=0.7 μm), which suggests a combined inhibitory effect of the two functional groups. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Registro:

Documento: Artículo
Título:Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii
Autor:Chao, M.N.; Li, C.; Storey, M.; Falcone, B.N.; Szajnman, S.H.; Bonesi, S.M.; Docampo, R.; Moreno, S.N.J.; 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, Department of Cellular Biology, University of Georgia, Athens, GA 30602, United States
Departamento de Química Orgánica and CIHIDECAR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, Buenos Aires, C1428EHA, Argentina
Palabras clave:antiprotozoal agents; drug discovery; enzymes; fluorine; inhibitors; 2 acetoxy 4 phenoxyphenol; 2 acetoxy 4 phenoxyphenoxyethanol; 2 acetoxy 4 phenoxyphenoxyethyl 4 toluenesulfonate; 2 acetoxy 4 phenoxyphenoxyethyl tetrahydro 2h pyran 2 yl ether; 2 acetoxy 4 phenoxyphenoxyethyl thiocyanate; 3 (2 fluorophenoxy)phenoxyethanol; 3 (2 fluorophenoxy)phenoxyethyl 4 toluenesulfonate; 3 (2 fluorophenoxy)phenoxyethyl tetrahydro 2h pyran 2 yl ether; 3 (2 fluorophenoxy)phenoxyethyl thiocyanate; 3 (3 fluorophenoxy)phenoxyethanol; 3 (3 fluorophenoxy)phenoxyethyl 4 toluenesulfonate; 3 (3 fluorophenoxy)phenoxyethyl tetrahydro 2h pyran 2 yl ether; 3 (3 fluorophenoxy)phenoxyethyl thiocyanate; 3 (4 fluorophenoxy)phenoxyethanol; 3 (4 fluorophenoxy)phenoxyethyl 4 toluenesulfonate; 3 (4 fluorophenoxy)phenoxyethyl tetrahydro 2h pyran 2 yl; 3 (4 fluorophenoxy)phenoxyethyl thiocyanate; 4 (2 fluorophenoxy)phenoxyethanol; 4 (2 fluorophenoxy)phenoxyethyl 4 toluenesulfonate; 4 (2 fluorophenoxy)phenoxyethyl tetrahydro 2h pyran 2 yl ether; 4 (2 fluorophenoxy)phenoxyethyl thiocyanate; 4 (4 pyridyl)oxyphenoxyethanol; 4 (4 pyridyl)oxyphenoxyethyl bromide; 4 (4 pyridyl)oxyphenoxyethyl tetrahydro 2h pyran 2 yl ether; 4 (4 pyridyl)oxyphenoxyethyl thiocyanate; 4 phenoxyphenoxyethyl thiocyanate; 4 phenoxyphenyl acetate; fluorine derivative; squalene synthase inhibitor; unclassified drug; unindexed drug; 4-phenoxyphenoxyethyl thiocyanate; antiparasitic agent; diphenyl ether derivative; fluorine; thiocyanic acid derivative; Article; controlled study; drug activity; drug design; drug potency; drug structure; drug synthesis; EC50; hydrogen bond; Michael addition; molecular dynamics; nonhuman; priority journal; Staudinger reaction; tissue culture cell; Toxoplasma gondii; Trypanosoma cruzi; Williamson reaction; animal; chemistry; Chlorocebus aethiops; computer simulation; drug effects; human; molecular model; sequence homology; Toxoplasma; Trypanosoma cruzi; Vero cell line; X ray crystallography; Animals; Antiparasitic Agents; Cercopithecus aethiops; Computer Simulation; Crystallography, X-Ray; Fluorine; Humans; Models, Molecular; Phenyl Ethers; Sequence Homology, Nucleic Acid; Thiocyanates; Toxoplasma; Trypanosoma cruzi; Vero Cells
Año:2016
Volumen:11
Número:24
Página de inicio:2690
Página de fin:2702
DOI: http://dx.doi.org/10.1002/cmdc.201600505
Título revista:ChemMedChem
Título revista abreviado:ChemMedChem
ISSN:18607179
CODEN:CHEMG
CAS:fluorine, 7782-41-4; 4-phenoxyphenoxyethyl thiocyanate; Antiparasitic Agents; Fluorine; Phenyl Ethers; Thiocyanates
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18607179_v11_n24_p2690_Chao

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Citas:

---------- APA ----------
Chao, M.N., Li, C., Storey, M., Falcone, B.N., Szajnman, S.H., Bonesi, S.M., Docampo, R.,..., Rodriguez, J.B. (2016) . Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii. ChemMedChem, 11(24), 2690-2702.
http://dx.doi.org/10.1002/cmdc.201600505
---------- CHICAGO ----------
Chao, M.N., Li, C., Storey, M., Falcone, B.N., Szajnman, S.H., Bonesi, S.M., et al. "Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii" . ChemMedChem 11, no. 24 (2016) : 2690-2702.
http://dx.doi.org/10.1002/cmdc.201600505
---------- MLA ----------
Chao, M.N., Li, C., Storey, M., Falcone, B.N., Szajnman, S.H., Bonesi, S.M., et al. "Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii" . ChemMedChem, vol. 11, no. 24, 2016, pp. 2690-2702.
http://dx.doi.org/10.1002/cmdc.201600505
---------- VANCOUVER ----------
Chao, M.N., Li, C., Storey, M., Falcone, B.N., Szajnman, S.H., Bonesi, S.M., et al. Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii. ChemMedChem. 2016;11(24):2690-2702.
http://dx.doi.org/10.1002/cmdc.201600505