New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase

Autores
Ferrer, Mariana; Li, Catherine; Gallizi, Melina; Stortz, Carlos Arturo; Szajnman, Sergio Hernan; Docampo, Roberto; Moreno, Silvia N. J.; Rodriguez, Juan Bautista
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED50 value of 4.7 μM against tachyzoites of T. gondii and an IC50 of 0.051 μM against TgFPPS.
Fil: Ferrer, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentina
Fil: Li, Catherine. University of Georgia; Estados Unidos
Fil: Gallizi, Melina. Georgia State University; Estados Unidos
Fil: Stortz, Carlos Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina
Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentina
Fil: Docampo, Roberto. University of Georgia; Estados Unidos
Fil: Moreno, Silvia N. J.. University of Georgia; 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 Aplicados a la Química Orgánica (i); Argentina
Materia
Bisphosphonic Acid
Recognition
Molecular Modeling
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:11336/8177
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/8177
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate SynthaseFerrer, MarianaLi, CatherineGallizi, MelinaStortz, Carlos ArturoSzajnman, Sergio HernanDocampo, RobertoMoreno, Silvia N. J.Rodriguez, Juan BautistaBisphosphonic AcidRecognitionMolecular Modelinghttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED50 value of 4.7 μM against tachyzoites of T. gondii and an IC50 of 0.051 μM against TgFPPS.Fil: Ferrer, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); ArgentinaFil: Li, Catherine. University of Georgia; Estados UnidosFil: Gallizi, Melina. Georgia State University; Estados UnidosFil: Stortz, Carlos Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; ArgentinaFil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); ArgentinaFil: Docampo, Roberto. University of Georgia; Estados UnidosFil: Moreno, Silvia N. J.. University of Georgia; Estados UnidosFil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); ArgentinaElsevier2014-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8177Ferrer, Mariana; Li, Catherine; Gallizi, Melina; Stortz, Carlos Arturo; Szajnman, Sergio Hernan; et al.; New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase; Elsevier; Bioorganic; 22; 1; 1-2014; 398-4050968-0896enginfo:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1016/j.bmc.2013.11.010info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0968089613009413info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:43:17Zoai:ri.conicet.gov.ar:11336/8177instacron: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:34982025-11-12 09:43:17.41CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
title New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
spellingShingle New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
Ferrer, Mariana
Bisphosphonic Acid
Recognition
Molecular Modeling
title_short New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
title_full New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
title_fullStr New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
title_full_unstemmed New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
title_sort New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase
dc.creator.none.fl_str_mv Ferrer, Mariana
Li, Catherine
Gallizi, Melina
Stortz, Carlos Arturo
Szajnman, Sergio Hernan
Docampo, Roberto
Moreno, Silvia N. J.
Rodriguez, Juan Bautista
author Ferrer, Mariana
author_facet Ferrer, Mariana
Li, Catherine
Gallizi, Melina
Stortz, Carlos Arturo
Szajnman, Sergio Hernan
Docampo, Roberto
Moreno, Silvia N. J.
Rodriguez, Juan Bautista
author_role author
author2 Li, Catherine
Gallizi, Melina
Stortz, Carlos Arturo
Szajnman, Sergio Hernan
Docampo, Roberto
Moreno, Silvia N. J.
Rodriguez, Juan Bautista
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Bisphosphonic Acid
Recognition
Molecular Modeling
topic Bisphosphonic Acid
Recognition
Molecular Modeling
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 part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED50 value of 4.7 μM against tachyzoites of T. gondii and an IC50 of 0.051 μM against TgFPPS.
Fil: Ferrer, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentina
Fil: Li, Catherine. University of Georgia; Estados Unidos
Fil: Gallizi, Melina. Georgia State University; Estados Unidos
Fil: Stortz, Carlos Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina
Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentina
Fil: Docampo, Roberto. University of Georgia; Estados Unidos
Fil: Moreno, Silvia N. J.. University of Georgia; 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 Aplicados a la Química Orgánica (i); Argentina
description As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED50 value of 4.7 μM against tachyzoites of T. gondii and an IC50 of 0.051 μM against TgFPPS.
publishDate 2014
dc.date.none.fl_str_mv 2014-01
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/11336/8177
Ferrer, Mariana; Li, Catherine; Gallizi, Melina; Stortz, Carlos Arturo; Szajnman, Sergio Hernan; et al.; New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase; Elsevier; Bioorganic; 22; 1; 1-2014; 398-405
0968-0896
url http://hdl.handle.net/11336/8177
identifier_str_mv Ferrer, Mariana; Li, Catherine; Gallizi, Melina; Stortz, Carlos Arturo; Szajnman, Sergio Hernan; et al.; New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Pyrophosphate Synthase; Elsevier; Bioorganic; 22; 1; 1-2014; 398-405
0968-0896
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1016/j.bmc.2013.11.010
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0968089613009413
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
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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 13.24909

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