Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi

Autores
Baldoni, Hector Armando; Sbaraglini, Maria Laura; Balcazar, Dario Emmanuel; Arias, Diego Gustavo; Guerrero, Sergio Adrian; Alba Soto, Catalina Dirney; Cieslik, Wioleta; Rogalska, Marta; Polanski, Jaroslaw; Enriz, Ricardo Daniel; Jampilek, Josef; Musiol, Robert
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
This study explores the rational design, synthesis, and biological evaluation of a series of thiosemicarbazone (TSC) derivatives as potential antitrypanosomal agents, with emphasis on substituent effects, molecular conformation, and steric interactions. In vitro screening against Trypanosoma cruzi (T. cruzi) and molecular docking studies were employed to elucidate structure-activity relationships (SAR) across different parasite life stages. A nitro-methoxy-substituted derivative exhibited the most potent cruzipain (CZP) inhibition, achieving near-complete suppression of epimastigote proliferation (EC50 = 0.36 μM), attributed to its favorable S-pose binding to the CZP active site. However, this compound displayed limited efficacy against the clinically relevant trypomastigote form. In contrast, brominated analogues demonstrated dual-stage activity, effectively targeting both trypomastigotes and epimastigotes through a CZP-independent mechanism. Tanimoto similarity clustering corroborated these findings, grouping nitro-methoxy compounds with epimastigote-selective profiles and distinguishing brominated scaffolds with broader antitrypanosomal potency. Steric complementarity and hydrophobicity emerged as key determinants of activity, with notable outliers such as an unsubstituted phenyl derivative and a chlorothiophene analogue displaying balanced stereoelectronic features. Importantly, assays on antioxidant defence enzymes, cytosolic tryparedoxin peroxidase (cTXNPx) and glutathione peroxidase type I (TcGPx-I), indicated no significant inhibition, excluding redox disruption as a major cytotoxic mechanism. These results highlight the potential of tailored TSC scaffolds for stage-specific chemotherapy and support a multi-targeted approach in the development of new treatments for Chagas disease.
Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Sbaraglini, Maria Laura. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Balcazar, Dario Emmanuel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentina
Fil: Arias, Diego Gustavo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Centro de Investigaciones sobre Endemias Nacionales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Guerrero, Sergio Adrian. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Microbiología General; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alba Soto, Catalina Dirney. Universidad Nacional del Nordeste. Facultad de Medicina. Cátedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cieslik, Wioleta. University of Silesia; Polonia
Fil: Rogalska, Marta. University of Silesia; Polonia
Fil: Polanski, Jaroslaw. University of Silesia; Polonia
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Jampilek, Josef. Palacky University Olomouc (upol);
Fil: Musiol, Robert. University of Silesia; Polonia
Materia
PIPERAZINYL THIOSEMICARBAZONES
CHAGAS DISEASE
TRYPANOSOMA CRUZI EPIMASTIGOTES
STRUCTURE-ACTIVITY RELATIONSHIPS
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:11336/290857
Acceder
id CONICETDig_6c8532aaffd068937567de239ee20527
oai_identifier_str oai:ri.conicet.gov.ar:11336/290857
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma CruziBaldoni, Hector ArmandoSbaraglini, Maria LauraBalcazar, Dario EmmanuelArias, Diego GustavoGuerrero, Sergio AdrianAlba Soto, Catalina DirneyCieslik, WioletaRogalska, MartaPolanski, JaroslawEnriz, Ricardo DanielJampilek, JosefMusiol, RobertPIPERAZINYL THIOSEMICARBAZONESCHAGAS DISEASETRYPANOSOMA CRUZI EPIMASTIGOTESSTRUCTURE-ACTIVITY RELATIONSHIPShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1This study explores the rational design, synthesis, and biological evaluation of a series of thiosemicarbazone (TSC) derivatives as potential antitrypanosomal agents, with emphasis on substituent effects, molecular conformation, and steric interactions. In vitro screening against Trypanosoma cruzi (T. cruzi) and molecular docking studies were employed to elucidate structure-activity relationships (SAR) across different parasite life stages. A nitro-methoxy-substituted derivative exhibited the most potent cruzipain (CZP) inhibition, achieving near-complete suppression of epimastigote proliferation (EC50 = 0.36 μM), attributed to its favorable S-pose binding to the CZP active site. However, this compound displayed limited efficacy against the clinically relevant trypomastigote form. In contrast, brominated analogues demonstrated dual-stage activity, effectively targeting both trypomastigotes and epimastigotes through a CZP-independent mechanism. Tanimoto similarity clustering corroborated these findings, grouping nitro-methoxy compounds with epimastigote-selective profiles and distinguishing brominated scaffolds with broader antitrypanosomal potency. Steric complementarity and hydrophobicity emerged as key determinants of activity, with notable outliers such as an unsubstituted phenyl derivative and a chlorothiophene analogue displaying balanced stereoelectronic features. Importantly, assays on antioxidant defence enzymes, cytosolic tryparedoxin peroxidase (cTXNPx) and glutathione peroxidase type I (TcGPx-I), indicated no significant inhibition, excluding redox disruption as a major cytotoxic mechanism. These results highlight the potential of tailored TSC scaffolds for stage-specific chemotherapy and support a multi-targeted approach in the development of new treatments for Chagas disease.Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Sbaraglini, Maria Laura. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Balcazar, Dario Emmanuel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Arias, Diego Gustavo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Centro de Investigaciones sobre Endemias Nacionales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guerrero, Sergio Adrian. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Microbiología General; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alba Soto, Catalina Dirney. Universidad Nacional del Nordeste. Facultad de Medicina. Cátedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cieslik, Wioleta. University of Silesia; PoloniaFil: Rogalska, Marta. University of Silesia; PoloniaFil: Polanski, Jaroslaw. University of Silesia; PoloniaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Jampilek, Josef. Palacky University Olomouc (upol);Fil: Musiol, Robert. University of Silesia; PoloniaElsevier2025-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/290857Baldoni, Hector Armando; Sbaraglini, Maria Laura; Balcazar, Dario Emmanuel; Arias, Diego Gustavo; Guerrero, Sergio Adrian; et al.; Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi; Elsevier; Social Science Research Network; 19; 182; 7-2025; 1-321556-5068CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5334367info:eu-repo/semantics/altIdentifier/doi/10.2139/ssrn.5334367info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:33:49Zoai:ri.conicet.gov.ar:11336/290857instacron: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:34982026-08-25 14:33:50.188CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
title Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
spellingShingle Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
Baldoni, Hector Armando
PIPERAZINYL THIOSEMICARBAZONES
CHAGAS DISEASE
TRYPANOSOMA CRUZI EPIMASTIGOTES
STRUCTURE-ACTIVITY RELATIONSHIPS
title_short Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
title_full Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
title_fullStr Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
title_full_unstemmed Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
title_sort Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi
dc.creator.none.fl_str_mv Baldoni, Hector Armando
Sbaraglini, Maria Laura
Balcazar, Dario Emmanuel
Arias, Diego Gustavo
Guerrero, Sergio Adrian
Alba Soto, Catalina Dirney
Cieslik, Wioleta
Rogalska, Marta
Polanski, Jaroslaw
Enriz, Ricardo Daniel
Jampilek, Josef
Musiol, Robert
author Baldoni, Hector Armando
author_facet Baldoni, Hector Armando
Sbaraglini, Maria Laura
Balcazar, Dario Emmanuel
Arias, Diego Gustavo
Guerrero, Sergio Adrian
Alba Soto, Catalina Dirney
Cieslik, Wioleta
Rogalska, Marta
Polanski, Jaroslaw
Enriz, Ricardo Daniel
Jampilek, Josef
Musiol, Robert
author_role author
author2 Sbaraglini, Maria Laura
Balcazar, Dario Emmanuel
Arias, Diego Gustavo
Guerrero, Sergio Adrian
Alba Soto, Catalina Dirney
Cieslik, Wioleta
Rogalska, Marta
Polanski, Jaroslaw
Enriz, Ricardo Daniel
Jampilek, Josef
Musiol, Robert
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PIPERAZINYL THIOSEMICARBAZONES
CHAGAS DISEASE
TRYPANOSOMA CRUZI EPIMASTIGOTES
STRUCTURE-ACTIVITY RELATIONSHIPS
topic PIPERAZINYL THIOSEMICARBAZONES
CHAGAS DISEASE
TRYPANOSOMA CRUZI EPIMASTIGOTES
STRUCTURE-ACTIVITY RELATIONSHIPS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv This study explores the rational design, synthesis, and biological evaluation of a series of thiosemicarbazone (TSC) derivatives as potential antitrypanosomal agents, with emphasis on substituent effects, molecular conformation, and steric interactions. In vitro screening against Trypanosoma cruzi (T. cruzi) and molecular docking studies were employed to elucidate structure-activity relationships (SAR) across different parasite life stages. A nitro-methoxy-substituted derivative exhibited the most potent cruzipain (CZP) inhibition, achieving near-complete suppression of epimastigote proliferation (EC50 = 0.36 μM), attributed to its favorable S-pose binding to the CZP active site. However, this compound displayed limited efficacy against the clinically relevant trypomastigote form. In contrast, brominated analogues demonstrated dual-stage activity, effectively targeting both trypomastigotes and epimastigotes through a CZP-independent mechanism. Tanimoto similarity clustering corroborated these findings, grouping nitro-methoxy compounds with epimastigote-selective profiles and distinguishing brominated scaffolds with broader antitrypanosomal potency. Steric complementarity and hydrophobicity emerged as key determinants of activity, with notable outliers such as an unsubstituted phenyl derivative and a chlorothiophene analogue displaying balanced stereoelectronic features. Importantly, assays on antioxidant defence enzymes, cytosolic tryparedoxin peroxidase (cTXNPx) and glutathione peroxidase type I (TcGPx-I), indicated no significant inhibition, excluding redox disruption as a major cytotoxic mechanism. These results highlight the potential of tailored TSC scaffolds for stage-specific chemotherapy and support a multi-targeted approach in the development of new treatments for Chagas disease.
Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Sbaraglini, Maria Laura. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Balcazar, Dario Emmanuel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentina
Fil: Arias, Diego Gustavo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Centro de Investigaciones sobre Endemias Nacionales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Guerrero, Sergio Adrian. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Microbiología General; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alba Soto, Catalina Dirney. Universidad Nacional del Nordeste. Facultad de Medicina. Cátedra de Microbiología, Parasitología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cieslik, Wioleta. University of Silesia; Polonia
Fil: Rogalska, Marta. University of Silesia; Polonia
Fil: Polanski, Jaroslaw. University of Silesia; Polonia
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Jampilek, Josef. Palacky University Olomouc (upol);
Fil: Musiol, Robert. University of Silesia; Polonia
description This study explores the rational design, synthesis, and biological evaluation of a series of thiosemicarbazone (TSC) derivatives as potential antitrypanosomal agents, with emphasis on substituent effects, molecular conformation, and steric interactions. In vitro screening against Trypanosoma cruzi (T. cruzi) and molecular docking studies were employed to elucidate structure-activity relationships (SAR) across different parasite life stages. A nitro-methoxy-substituted derivative exhibited the most potent cruzipain (CZP) inhibition, achieving near-complete suppression of epimastigote proliferation (EC50 = 0.36 μM), attributed to its favorable S-pose binding to the CZP active site. However, this compound displayed limited efficacy against the clinically relevant trypomastigote form. In contrast, brominated analogues demonstrated dual-stage activity, effectively targeting both trypomastigotes and epimastigotes through a CZP-independent mechanism. Tanimoto similarity clustering corroborated these findings, grouping nitro-methoxy compounds with epimastigote-selective profiles and distinguishing brominated scaffolds with broader antitrypanosomal potency. Steric complementarity and hydrophobicity emerged as key determinants of activity, with notable outliers such as an unsubstituted phenyl derivative and a chlorothiophene analogue displaying balanced stereoelectronic features. Importantly, assays on antioxidant defence enzymes, cytosolic tryparedoxin peroxidase (cTXNPx) and glutathione peroxidase type I (TcGPx-I), indicated no significant inhibition, excluding redox disruption as a major cytotoxic mechanism. These results highlight the potential of tailored TSC scaffolds for stage-specific chemotherapy and support a multi-targeted approach in the development of new treatments for Chagas disease.
publishDate 2025
dc.date.none.fl_str_mv 2025-07
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/11336/290857
Baldoni, Hector Armando; Sbaraglini, Maria Laura; Balcazar, Dario Emmanuel; Arias, Diego Gustavo; Guerrero, Sergio Adrian; et al.; Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi; Elsevier; Social Science Research Network; 19; 182; 7-2025; 1-32
1556-5068
CONICET Digital
CONICET
url http://hdl.handle.net/11336/290857
identifier_str_mv Baldoni, Hector Armando; Sbaraglini, Maria Laura; Balcazar, Dario Emmanuel; Arias, Diego Gustavo; Guerrero, Sergio Adrian; et al.; Design and Evaluation of Novel Multi-Target, Stage-Specific Piperazinyl Thiosemicarbazones Against Trypanosoma Cruzi; Elsevier; Social Science Research Network; 19; 182; 7-2025; 1-32
1556-5068
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://papers.ssrn.com/sol3/papers.cfm?abstract_id=5334367
info:eu-repo/semantics/altIdentifier/doi/10.2139/ssrn.5334367
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
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
_version_ 1874774181340512256
score 13.24418

Publicaciones similares