Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.bmcl.2023.129123 http://hdl.handle.net/11449/246723 |
Resumo: | Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure–activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT. |
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Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma bruceiAntiparasitic activityCurcuminoidCytotoxicityDibenzylideneacetoneTrypanosoma bruceiTrypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure–activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Center for Discovery and Innovation in Parasitic Diseases Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego, La JollaLaboratory Affiliated with the Institute Pasteur Italy – Cenci Bolognetti Foundation Department of Drug Chemistry and Technologies Sapienza University of RomeInstitute of Biosciences Humanities and Exact Sciences São Paulo State University, São José do Rio Preto, SPFaculty of Philosophy Sciences and Letters of Ribeirão Preto University of São Paulo, SPResearch Group on Natural Products Center for Research in Sciences and Technology University of Franca, SPInstitute of Biosciences Humanities and Exact Sciences São Paulo State University, São José do Rio Preto, SPUniversity of CaliforniaSapienza University of RomeUniversidade Estadual Paulista (UNESP)Universidade de São Paulo (USP)University of FrancaFrancisco, Karol R.Monti, LudovicaYang, WenqianPark, HayoungLiu, Lawrence J.Watkins, KaitlynAmarasinghe, Dilini K.Nalli, MariannaRoberto Polaquini, Carlos [UNESP]Regasini, Luis O. [UNESP]Eduardo Miller Crotti, AntônioSilvestri, RomanoGuidi Magalhães, LizandraCaffrey, Conor R.2023-07-29T12:48:43Z2023-07-29T12:48:43Z2023-02-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.bmcl.2023.129123Bioorganic and Medicinal Chemistry Letters, v. 81.1464-34050960-894Xhttp://hdl.handle.net/11449/24672310.1016/j.bmcl.2023.1291232-s2.0-85146832382Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBioorganic and Medicinal Chemistry Lettersinfo:eu-repo/semantics/openAccess2023-07-29T12:48:43Zoai:repositorio.unesp.br:11449/246723Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T13:36:07.705389Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
title |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
spellingShingle |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei Francisco, Karol R. Antiparasitic activity Curcuminoid Cytotoxicity Dibenzylideneacetone Trypanosoma brucei |
title_short |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
title_full |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
title_fullStr |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
title_full_unstemmed |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
title_sort |
Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei |
author |
Francisco, Karol R. |
author_facet |
Francisco, Karol R. Monti, Ludovica Yang, Wenqian Park, Hayoung Liu, Lawrence J. Watkins, Kaitlyn Amarasinghe, Dilini K. Nalli, Marianna Roberto Polaquini, Carlos [UNESP] Regasini, Luis O. [UNESP] Eduardo Miller Crotti, Antônio Silvestri, Romano Guidi Magalhães, Lizandra Caffrey, Conor R. |
author_role |
author |
author2 |
Monti, Ludovica Yang, Wenqian Park, Hayoung Liu, Lawrence J. Watkins, Kaitlyn Amarasinghe, Dilini K. Nalli, Marianna Roberto Polaquini, Carlos [UNESP] Regasini, Luis O. [UNESP] Eduardo Miller Crotti, Antônio Silvestri, Romano Guidi Magalhães, Lizandra Caffrey, Conor R. |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
University of California Sapienza University of Rome Universidade Estadual Paulista (UNESP) Universidade de São Paulo (USP) University of Franca |
dc.contributor.author.fl_str_mv |
Francisco, Karol R. Monti, Ludovica Yang, Wenqian Park, Hayoung Liu, Lawrence J. Watkins, Kaitlyn Amarasinghe, Dilini K. Nalli, Marianna Roberto Polaquini, Carlos [UNESP] Regasini, Luis O. [UNESP] Eduardo Miller Crotti, Antônio Silvestri, Romano Guidi Magalhães, Lizandra Caffrey, Conor R. |
dc.subject.por.fl_str_mv |
Antiparasitic activity Curcuminoid Cytotoxicity Dibenzylideneacetone Trypanosoma brucei |
topic |
Antiparasitic activity Curcuminoid Cytotoxicity Dibenzylideneacetone Trypanosoma brucei |
description |
Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure–activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-29T12:48:43Z 2023-07-29T12:48:43Z 2023-02-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.bmcl.2023.129123 Bioorganic and Medicinal Chemistry Letters, v. 81. 1464-3405 0960-894X http://hdl.handle.net/11449/246723 10.1016/j.bmcl.2023.129123 2-s2.0-85146832382 |
url |
http://dx.doi.org/10.1016/j.bmcl.2023.129123 http://hdl.handle.net/11449/246723 |
identifier_str_mv |
Bioorganic and Medicinal Chemistry Letters, v. 81. 1464-3405 0960-894X 10.1016/j.bmcl.2023.129123 2-s2.0-85146832382 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Bioorganic and Medicinal Chemistry Letters |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808128253322330112 |