Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase

Autores
Aripirala, Srinivas; Szajnman, Sergio Hernan; Jakoncic, Jean; Rodriguez, Juan Bautista; Docampo, Roberto; Gabelli, Sandra B.; Amzel, L. Mario
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC 50 values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.
Fil: Aripirala, Srinivas. University Johns Hopkins; Estados Unidos
Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Jakoncic, Jean. National Synchrotron Light Source; Estados Unidos
Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Docampo, Roberto. University of Georgia; Estados Unidos
Fil: Gabelli, Sandra B.. University Johns Hopkins; Estados Unidos
Fil: Amzel, L. Mario. University Johns Hopkins; Estados Unidos
Materia
Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
Farnesyl Diphosphate Synthase
Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
Nivel de accesibilidad
acceso abierto
Condiciones de uso
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:11336/85637
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/85637
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthaseAripirala, SrinivasSzajnman, Sergio HernanJakoncic, JeanRodriguez, Juan BautistaDocampo, RobertoGabelli, Sandra B.Amzel, L. MarioAlkylaminoethyl-1,1-bisphosphonatesTrypanosoma cruziFarnesyl Diphosphate SynthaseAlkylaminoethyl-1,1-bisphosphonatesTrypanosoma cruzihttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC 50 values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.Fil: Aripirala, Srinivas. University Johns Hopkins; Estados UnidosFil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Jakoncic, Jean. National Synchrotron Light Source; Estados UnidosFil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Docampo, Roberto. University of Georgia; Estados UnidosFil: Gabelli, Sandra B.. University Johns Hopkins; Estados UnidosFil: Amzel, L. Mario. University Johns Hopkins; Estados UnidosAmerican Chemical Society2012-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85637Aripirala, Srinivas; Szajnman, Sergio Hernan; Jakoncic, Jean; Rodriguez, Juan Bautista; Docampo, Roberto; et al.; Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase; American Chemical Society; Journal of Medicinal Chemistry; 55; 14; 7-2012; 6445-64540022-2623CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jm300425yinfo:eu-repo/semantics/altIdentifier/doi/10.1021/jm300425yinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:56:16Zoai:ri.conicet.gov.ar:11336/85637instacron: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 09:56:16.999CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
title Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
spellingShingle Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
Aripirala, Srinivas
Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
Farnesyl Diphosphate Synthase
Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
title_short Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
title_full Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
title_fullStr Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
title_full_unstemmed Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
title_sort Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
dc.creator.none.fl_str_mv Aripirala, Srinivas
Szajnman, Sergio Hernan
Jakoncic, Jean
Rodriguez, Juan Bautista
Docampo, Roberto
Gabelli, Sandra B.
Amzel, L. Mario
author Aripirala, Srinivas
author_facet Aripirala, Srinivas
Szajnman, Sergio Hernan
Jakoncic, Jean
Rodriguez, Juan Bautista
Docampo, Roberto
Gabelli, Sandra B.
Amzel, L. Mario
author_role author
author2 Szajnman, Sergio Hernan
Jakoncic, Jean
Rodriguez, Juan Bautista
Docampo, Roberto
Gabelli, Sandra B.
Amzel, L. Mario
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
Farnesyl Diphosphate Synthase
Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
topic Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
Farnesyl Diphosphate Synthase
Alkylaminoethyl-1,1-bisphosphonates
Trypanosoma cruzi
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC 50 values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.
Fil: Aripirala, Srinivas. University Johns Hopkins; Estados Unidos
Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Jakoncic, Jean. National Synchrotron Light Source; Estados Unidos
Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Docampo, Roberto. University of Georgia; Estados Unidos
Fil: Gabelli, Sandra B.. University Johns Hopkins; Estados Unidos
Fil: Amzel, L. Mario. University Johns Hopkins; Estados Unidos
description Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC 50 values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.
publishDate 2012
dc.date.none.fl_str_mv 2012-07
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/11336/85637
Aripirala, Srinivas; Szajnman, Sergio Hernan; Jakoncic, Jean; Rodriguez, Juan Bautista; Docampo, Roberto; et al.; Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase; American Chemical Society; Journal of Medicinal Chemistry; 55; 14; 7-2012; 6445-6454
0022-2623
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85637
identifier_str_mv Aripirala, Srinivas; Szajnman, Sergio Hernan; Jakoncic, Jean; Rodriguez, Juan Bautista; Docampo, Roberto; et al.; Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase; American Chemical Society; Journal of Medicinal Chemistry; 55; 14; 7-2012; 6445-6454
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/jm300425y
info:eu-repo/semantics/altIdentifier/doi/10.1021/jm300425y
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
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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