Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives

Autores
Slafer, Brian W.; Dessoy, Marco A.; de Oliveira, Ramon G.; Mollo, María Cruz; Lee, Eun; Matheeussen, An; Maes, Louis; Caljon, Guy; Ferreira, Leonardo L. G.; Krogh, Renata; Andricopulo, Adriano D.; Cruz, Luiza R.; Mowbray, Charles E.; Kratz, Jadel M.; Dias, Luiz C.
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.
Fil: Slafer, Brian W.. Universidade Estadual de Campinas; Brasil
Fil: Dessoy, Marco A.. Universidade Estadual de Campinas; Brasil
Fil: de Oliveira, Ramon G.. Universidade Estadual de Campinas; Brasil
Fil: Mollo, María Cruz. Universidade Estadual de Campinas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lee, Eun. Universidade Estadual de Campinas; Brasil
Fil: Matheeussen, An. Universidade Estadual de Campinas; Brasil
Fil: Maes, Louis. Universidade Estadual de Campinas; Brasil
Fil: Caljon, Guy. Universiteit Antwerp; Bélgica
Fil: Ferreira, Leonardo L. G.. Universidade de Sao Paulo; Brasil
Fil: Krogh, Renata. Universidade de Sao Paulo; Brasil
Fil: Andricopulo, Adriano D.. Universidade de Sao Paulo; Brasil
Fil: Cruz, Luiza R.. No especifíca;
Fil: Mowbray, Charles E.. No especifíca;
Fil: Kratz, Jadel M.. No especifíca;
Fil: Dias, Luiz C.. Universidade Estadual de Campinas; Brasil
Materia
TRYPANOSOMA CRUZI
DRUG DISCOVERY
CHAGAS
MULTIPARAMETRIC OPTIMIZATION
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:11336/236058
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/236058
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine DerivativesSlafer, Brian W.Dessoy, Marco A.de Oliveira, Ramon G.Mollo, María CruzLee, EunMatheeussen, AnMaes, LouisCaljon, GuyFerreira, Leonardo L. G.Krogh, RenataAndricopulo, Adriano D.Cruz, Luiza R.Mowbray, Charles E.Kratz, Jadel M.Dias, Luiz C.TRYPANOSOMA CRUZIDRUG DISCOVERYCHAGASMULTIPARAMETRIC OPTIMIZATIONhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.Fil: Slafer, Brian W.. Universidade Estadual de Campinas; BrasilFil: Dessoy, Marco A.. Universidade Estadual de Campinas; BrasilFil: de Oliveira, Ramon G.. Universidade Estadual de Campinas; BrasilFil: Mollo, María Cruz. Universidade Estadual de Campinas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lee, Eun. Universidade Estadual de Campinas; BrasilFil: Matheeussen, An. Universidade Estadual de Campinas; BrasilFil: Maes, Louis. Universidade Estadual de Campinas; BrasilFil: Caljon, Guy. Universiteit Antwerp; BélgicaFil: Ferreira, Leonardo L. G.. Universidade de Sao Paulo; BrasilFil: Krogh, Renata. Universidade de Sao Paulo; BrasilFil: Andricopulo, Adriano D.. Universidade de Sao Paulo; BrasilFil: Cruz, Luiza R.. No especifíca;Fil: Mowbray, Charles E.. No especifíca;Fil: Kratz, Jadel M.. No especifíca;Fil: Dias, Luiz C.. Universidade Estadual de Campinas; BrasilAmerican Chemical Society2024-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/236058Slafer, Brian W.; Dessoy, Marco A.; de Oliveira, Ramon G.; Mollo, María Cruz; Lee, Eun; et al.; Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives; American Chemical Society; ACS Omega; 5-2024; 1-112470-1343CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acsomega.4c01919info:eu-repo/semantics/altIdentifier/doi/10.1021/acsomega.4c01919info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:34:47Zoai:ri.conicet.gov.ar:11336/236058instacron: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 10:34:47.671CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
title Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
spellingShingle Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
Slafer, Brian W.
TRYPANOSOMA CRUZI
DRUG DISCOVERY
CHAGAS
MULTIPARAMETRIC OPTIMIZATION
title_short Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
title_full Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
title_fullStr Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
title_full_unstemmed Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
title_sort Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
dc.creator.none.fl_str_mv Slafer, Brian W.
Dessoy, Marco A.
de Oliveira, Ramon G.
Mollo, María Cruz
Lee, Eun
Matheeussen, An
Maes, Louis
Caljon, Guy
Ferreira, Leonardo L. G.
Krogh, Renata
Andricopulo, Adriano D.
Cruz, Luiza R.
Mowbray, Charles E.
Kratz, Jadel M.
Dias, Luiz C.
author Slafer, Brian W.
author_facet Slafer, Brian W.
Dessoy, Marco A.
de Oliveira, Ramon G.
Mollo, María Cruz
Lee, Eun
Matheeussen, An
Maes, Louis
Caljon, Guy
Ferreira, Leonardo L. G.
Krogh, Renata
Andricopulo, Adriano D.
Cruz, Luiza R.
Mowbray, Charles E.
Kratz, Jadel M.
Dias, Luiz C.
author_role author
author2 Dessoy, Marco A.
de Oliveira, Ramon G.
Mollo, María Cruz
Lee, Eun
Matheeussen, An
Maes, Louis
Caljon, Guy
Ferreira, Leonardo L. G.
Krogh, Renata
Andricopulo, Adriano D.
Cruz, Luiza R.
Mowbray, Charles E.
Kratz, Jadel M.
Dias, Luiz C.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TRYPANOSOMA CRUZI
DRUG DISCOVERY
CHAGAS
MULTIPARAMETRIC OPTIMIZATION
topic TRYPANOSOMA CRUZI
DRUG DISCOVERY
CHAGAS
MULTIPARAMETRIC OPTIMIZATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.
Fil: Slafer, Brian W.. Universidade Estadual de Campinas; Brasil
Fil: Dessoy, Marco A.. Universidade Estadual de Campinas; Brasil
Fil: de Oliveira, Ramon G.. Universidade Estadual de Campinas; Brasil
Fil: Mollo, María Cruz. Universidade Estadual de Campinas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lee, Eun. Universidade Estadual de Campinas; Brasil
Fil: Matheeussen, An. Universidade Estadual de Campinas; Brasil
Fil: Maes, Louis. Universidade Estadual de Campinas; Brasil
Fil: Caljon, Guy. Universiteit Antwerp; Bélgica
Fil: Ferreira, Leonardo L. G.. Universidade de Sao Paulo; Brasil
Fil: Krogh, Renata. Universidade de Sao Paulo; Brasil
Fil: Andricopulo, Adriano D.. Universidade de Sao Paulo; Brasil
Fil: Cruz, Luiza R.. No especifíca;
Fil: Mowbray, Charles E.. No especifíca;
Fil: Kratz, Jadel M.. No especifíca;
Fil: Dias, Luiz C.. Universidade Estadual de Campinas; Brasil
description Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.
publishDate 2024
dc.date.none.fl_str_mv 2024-05
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/11336/236058
Slafer, Brian W.; Dessoy, Marco A.; de Oliveira, Ramon G.; Mollo, María Cruz; Lee, Eun; et al.; Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives; American Chemical Society; ACS Omega; 5-2024; 1-11
2470-1343
CONICET Digital
CONICET
url http://hdl.handle.net/11336/236058
identifier_str_mv Slafer, Brian W.; Dessoy, Marco A.; de Oliveira, Ramon G.; Mollo, María Cruz; Lee, Eun; et al.; Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives; American Chemical Society; ACS Omega; 5-2024; 1-11
2470-1343
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/acsomega.4c01919
info:eu-repo/semantics/altIdentifier/doi/10.1021/acsomega.4c01919
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
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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