Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii

Autores
Galaka, Tamila Pavlivna; Falcone, Bruno Nicolas; Li, Catherine; Szajnman, Sergio Hernan; Moreno, Silvia N.J.; Docampo, Roberto; Rodriguez, Juan Bautista
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21–33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47–49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54–56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.
Fil: Galaka, Tamila Pavlivna. 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
Fil: Falcone, Bruno Nicolas. 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
Fil: Li, Catherine. University of Georgia; 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
Fil: Moreno, Silvia N.J.. University of Georgia; Estados Unidos
Fil: Docampo, Roberto. 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 en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Materia
Trypanosoma cruzi
Toxoplasma gondii
Bisphosphonates
Farnesyl diphosphate synthase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/121041

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network_name_str CONICET Digital (CONICET)
spelling Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondiiGalaka, Tamila PavlivnaFalcone, Bruno NicolasLi, CatherineSzajnman, Sergio HernanMoreno, Silvia N.J.Docampo, RobertoRodriguez, Juan BautistaTrypanosoma cruziToxoplasma gondiiBisphosphonatesFarnesyl diphosphate synthasehttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21–33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47–49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54–56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.Fil: Galaka, Tamila Pavlivna. 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; ArgentinaFil: Falcone, Bruno Nicolas. 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; ArgentinaFil: Li, Catherine. University of Georgia; 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; ArgentinaFil: Moreno, Silvia N.J.. University of Georgia; Estados UnidosFil: Docampo, Roberto. 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 en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaPergamon-Elsevier Science Ltd2019-08info: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/11336/121041Galaka, Tamila Pavlivna; Falcone, Bruno Nicolas; Li, Catherine; Szajnman, Sergio Hernan; Moreno, Silvia N.J.; et al.; Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 27; 16; 8-2019; 3663-36730968-0896CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0968089619307400info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2019.07.004info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660996/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:37:56Zoai:ri.conicet.gov.ar:11336/121041instacron: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:34982025-10-22 11:37:56.91CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
title Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
spellingShingle Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
Galaka, Tamila Pavlivna
Trypanosoma cruzi
Toxoplasma gondii
Bisphosphonates
Farnesyl diphosphate synthase
title_short Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
title_full Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
title_fullStr Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
title_full_unstemmed Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
title_sort Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
dc.creator.none.fl_str_mv Galaka, Tamila Pavlivna
Falcone, Bruno Nicolas
Li, Catherine
Szajnman, Sergio Hernan
Moreno, Silvia N.J.
Docampo, Roberto
Rodriguez, Juan Bautista
author Galaka, Tamila Pavlivna
author_facet Galaka, Tamila Pavlivna
Falcone, Bruno Nicolas
Li, Catherine
Szajnman, Sergio Hernan
Moreno, Silvia N.J.
Docampo, Roberto
Rodriguez, Juan Bautista
author_role author
author2 Falcone, Bruno Nicolas
Li, Catherine
Szajnman, Sergio Hernan
Moreno, Silvia N.J.
Docampo, Roberto
Rodriguez, Juan Bautista
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Trypanosoma cruzi
Toxoplasma gondii
Bisphosphonates
Farnesyl diphosphate synthase
topic Trypanosoma cruzi
Toxoplasma gondii
Bisphosphonates
Farnesyl diphosphate synthase
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 an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21–33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47–49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54–56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.
Fil: Galaka, Tamila Pavlivna. 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
Fil: Falcone, Bruno Nicolas. 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
Fil: Li, Catherine. University of Georgia; 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
Fil: Moreno, Silvia N.J.. University of Georgia; Estados Unidos
Fil: Docampo, Roberto. 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 en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
description As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21–33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47–49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54–56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.
publishDate 2019
dc.date.none.fl_str_mv 2019-08
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/11336/121041
Galaka, Tamila Pavlivna; Falcone, Bruno Nicolas; Li, Catherine; Szajnman, Sergio Hernan; Moreno, Silvia N.J.; et al.; Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 27; 16; 8-2019; 3663-3673
0968-0896
CONICET Digital
CONICET
url http://hdl.handle.net/11336/121041
identifier_str_mv Galaka, Tamila Pavlivna; Falcone, Bruno Nicolas; Li, Catherine; Szajnman, Sergio Hernan; Moreno, Silvia N.J.; et al.; Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 27; 16; 8-2019; 3663-3673
0968-0896
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://linkinghub.elsevier.com/retrieve/pii/S0968089619307400
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2019.07.004
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660996/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
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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