Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation
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 dis...
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2017
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v25_n24_p6435_Chao http://hdl.handle.net/20.500.12110/paper_09680896_v25_n24_p6435_Chao |
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paper:paper_09680896_v25_n24_p6435_Chao2023-06-08T15:58:58Z Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation 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 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 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v25_n24_p6435_Chao http://hdl.handle.net/20.500.12110/paper_09680896_v25_n24_p6435_Chao |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation |
| topic_facet |
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 |
| description |
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 |
| title |
Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation |
| title_short |
Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation |
| title_full |
Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation |
| title_fullStr |
Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation |
| title_full_unstemmed |
Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation |
| title_sort |
selenium-containing analogues of wc-9 are extremely potent inhibitors of trypanosoma cruzi proliferation |
| publishDate |
2017 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v25_n24_p6435_Chao http://hdl.handle.net/20.500.12110/paper_09680896_v25_n24_p6435_Chao |
| _version_ |
1768542654854856704 |