Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation

Autores
Szajnman, Sergio Hernan; Yan, Wen; Bailey, Brian N.; Docampo, Roberto; Elhalem, Eleonora; Rodriguez, Juan Bautista
Año de publicación
2000
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts.
Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Yan, Wen. University of Illinois at Urbana; Estados Unidos
Fil: Bailey, Brian N.. University of Illinois at Urbana; Estados Unidos
Fil: Docampo, Roberto. University of Illinois at Urbana; Estados Unidos
Fil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
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acceso abierto
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/85791
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/85791
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferationSzajnman, Sergio HernanYan, WenBailey, Brian N.Docampo, RobertoElhalem, EleonoraRodriguez, Juan Bautistahttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts.Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Yan, Wen. University of Illinois at Urbana; Estados UnidosFil: Bailey, Brian N.. University of Illinois at Urbana; Estados UnidosFil: Docampo, Roberto. University of Illinois at Urbana; Estados UnidosFil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaAmerican Chemical Society2000-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85791Szajnman, Sergio Hernan; Yan, Wen; Bailey, Brian N.; Docampo, Roberto; Elhalem, Eleonora; et al.; Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation; American Chemical Society; Journal of Medicinal Chemistry; 43; 9; 12-2000; 1826-18400022-2623CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jm9905007info:eu-repo/semantics/altIdentifier/doi/10.1021/jm9905007info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:46:29Zoai:ri.conicet.gov.ar:11336/85791instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:46:29.574CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
title Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
spellingShingle Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
Szajnman, Sergio Hernan
title_short Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
title_full Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
title_fullStr Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
title_full_unstemmed Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
title_sort Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
dc.creator.none.fl_str_mv Szajnman, Sergio Hernan
Yan, Wen
Bailey, Brian N.
Docampo, Roberto
Elhalem, Eleonora
Rodriguez, Juan Bautista
author Szajnman, Sergio Hernan
author_facet Szajnman, Sergio Hernan
Yan, Wen
Bailey, Brian N.
Docampo, Roberto
Elhalem, Eleonora
Rodriguez, Juan Bautista
author_role author
author2 Yan, Wen
Bailey, Brian N.
Docampo, Roberto
Elhalem, Eleonora
Rodriguez, Juan Bautista
author2_role author
author
author
author
author
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts.
Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Yan, Wen. University of Illinois at Urbana; Estados Unidos
Fil: Bailey, Brian N.. University of Illinois at Urbana; Estados Unidos
Fil: Docampo, Roberto. University of Illinois at Urbana; Estados Unidos
Fil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
description As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts.
publishDate 2000
dc.date.none.fl_str_mv 2000-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/85791
Szajnman, Sergio Hernan; Yan, Wen; Bailey, Brian N.; Docampo, Roberto; Elhalem, Eleonora; et al.; Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation; American Chemical Society; Journal of Medicinal Chemistry; 43; 9; 12-2000; 1826-1840
0022-2623
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85791
identifier_str_mv Szajnman, Sergio Hernan; Yan, Wen; Bailey, Brian N.; Docampo, Roberto; Elhalem, Eleonora; et al.; Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation; American Chemical Society; Journal of Medicinal Chemistry; 43; 9; 12-2000; 1826-1840
0022-2623
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jm9905007
info:eu-repo/semantics/altIdentifier/doi/10.1021/jm9905007
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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