Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities

Detalhes bibliográficos
Autor(a) principal: Sulik, Michał
Data de Publicação: 2023
Outros Autores: Fontinha, Diana, Steverding, Dietmar, Sobczak, Szymon, Antoszczak, Michał, Prudêncio, Miguel, Huczyński, Adam
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/61140
Resumo: © 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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spelling Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activitiesC13-epi-amide derivativesIvermectinPlasmodicidal activityPlasmodium bergheiTrypanocidal activityTrypanosoma brucei© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Ivermectin is a sixteen-membered macrolactone "wonder drug" of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used for almost four decades in the treatment of various parasitic diseases in humans and animals. In this paper, we describe the synthesis of the first-in-class ivermectin derivatives obtained via derivatization of the C13 position, along with the unexpected rearrangement of the oxahydrindene (hexahydrobenzofuran) unit of the macrolide ring. The structural investigation of the rearrangement has been performed using the single-crystal X-ray diffraction method. The antiparasitic and cytotoxic activities of the newly synthesized derivatives were determined in vitro with the bloodstream form of Trypanosoma brucei brucei, the hepatic stage of Plasmodium berghei, and human leukemia HL-60 cells. The compounds with the highest trypanocidal activity were the C13-epi-2-chloroacetamide analogs of native (6h) or rearranged (7h) ivermectin. Both 6h and 7h displayed trypanocidal activities within a similar mid-nanomolar concentration range as the commercially used trypanocides suramin and ethidium bromide. Furthermore, 6h and 7h exhibited a comparable cytotoxic to trypanocidal ratio as the reference drug ethidium bromide. The double-modified compound 7a (C13-epi-acetamide of rearranged ivermectin) exhibited the highest activity against P. berghei grown in human hepatoma cells, which was 2.5 times higher than that of ivermectin. The findings of this study suggest that C13-epi-amide derivatives of ivermectin are suitable leads in the rational development of new antiparasitic agents.The synthesis of ivermectin derivatives was financially supported by a Diamond Grant (0159/DIA/2020/49) funded by the Polish Ministry of Education and Science (MEiN) to M.S. D.F. wishes to acknowledge FCT ‒ Fundação para a Ciência e Tecnologia, I.P., for the financial support (project reference 2022.02624.PTDC).ElsevierRepositório da Universidade de LisboaSulik, MichałFontinha, DianaSteverding, DietmarSobczak, SzymonAntoszczak, MichałPrudêncio, MiguelHuczyński, Adam2023-12-05T12:31:32Z20242024-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/61140engEur J Med Chem. 2024 Jan 5:263:1159510223-523410.1016/j.ejmech.2023.1159511768-3254info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-12-11T01:16:23Zoai:repositorio.ul.pt:10451/61140Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:42:11.119222Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
title Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
spellingShingle Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
Sulik, Michał
C13-epi-amide derivatives
Ivermectin
Plasmodicidal activity
Plasmodium berghei
Trypanocidal activity
Trypanosoma brucei
title_short Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
title_full Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
title_fullStr Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
title_full_unstemmed Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
title_sort Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
author Sulik, Michał
author_facet Sulik, Michał
Fontinha, Diana
Steverding, Dietmar
Sobczak, Szymon
Antoszczak, Michał
Prudêncio, Miguel
Huczyński, Adam
author_role author
author2 Fontinha, Diana
Steverding, Dietmar
Sobczak, Szymon
Antoszczak, Michał
Prudêncio, Miguel
Huczyński, Adam
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Sulik, Michał
Fontinha, Diana
Steverding, Dietmar
Sobczak, Szymon
Antoszczak, Michał
Prudêncio, Miguel
Huczyński, Adam
dc.subject.por.fl_str_mv C13-epi-amide derivatives
Ivermectin
Plasmodicidal activity
Plasmodium berghei
Trypanocidal activity
Trypanosoma brucei
topic C13-epi-amide derivatives
Ivermectin
Plasmodicidal activity
Plasmodium berghei
Trypanocidal activity
Trypanosoma brucei
description © 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
publishDate 2023
dc.date.none.fl_str_mv 2023-12-05T12:31:32Z
2024
2024-01-01T00:00:00Z
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://hdl.handle.net/10451/61140
url http://hdl.handle.net/10451/61140
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Eur J Med Chem. 2024 Jan 5:263:115951
0223-5234
10.1016/j.ejmech.2023.115951
1768-3254
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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