Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii
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...
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2016
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18607179_v11_n24_p2690_Chao http://hdl.handle.net/20.500.12110/paper_18607179_v11_n24_p2690_Chao |
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paper:paper_18607179_v11_n24_p2690_Chao |
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dspace |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Szajnman, Sergio Hernán Bonesi, Sergio Mauricio Moreno, Silvia N. J. Rodríguez, Juan Bautista Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii |
| topic_facet |
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 |
| description |
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 |
| author |
Szajnman, Sergio Hernán Bonesi, Sergio Mauricio Moreno, Silvia N. J. Rodríguez, Juan Bautista |
| author_facet |
Szajnman, Sergio Hernán Bonesi, Sergio Mauricio Moreno, Silvia N. J. Rodríguez, Juan Bautista |
| author_sort |
Szajnman, Sergio Hernán |
| title |
Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii |
| title_short |
Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii |
| title_full |
Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii |
| title_fullStr |
Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii |
| title_full_unstemmed |
Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii |
| title_sort |
activity of fluorine-containing analogues of wc-9 and structurally related analogues against two intracellular parasites: trypanosoma cruzi and toxoplasma gondii |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18607179_v11_n24_p2690_Chao http://hdl.handle.net/20.500.12110/paper_18607179_v11_n24_p2690_Chao |
| work_keys_str_mv |
AT szajnmansergiohernan activityoffluorinecontaininganaloguesofwc9andstructurallyrelatedanaloguesagainsttwointracellularparasitestrypanosomacruziandtoxoplasmagondii AT bonesisergiomauricio activityoffluorinecontaininganaloguesofwc9andstructurallyrelatedanaloguesagainsttwointracellularparasitestrypanosomacruziandtoxoplasmagondii AT morenosilvianj activityoffluorinecontaininganaloguesofwc9andstructurallyrelatedanaloguesagainsttwointracellularparasitestrypanosomacruziandtoxoplasmagondii AT rodriguezjuanbautista activityoffluorinecontaininganaloguesofwc9andstructurallyrelatedanaloguesagainsttwointracellularparasitestrypanosomacruziandtoxoplasmagondii |
| _version_ |
1768543007682854912 |
| spelling |
paper:paper_18607179_v11_n24_p2690_Chao2023-06-08T16:29:28Z Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii Szajnman, Sergio Hernán Bonesi, Sergio Mauricio Moreno, Silvia N. J. Rodríguez, Juan Bautista 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 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 Fil:Szajnman, S.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Bonesi, S.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Moreno, S.N.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rodriguez, J.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18607179_v11_n24_p2690_Chao http://hdl.handle.net/20.500.12110/paper_18607179_v11_n24_p2690_Chao |