Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates

Detalhes bibliográficos
Autor(a) principal: Alves, Américo
Data de Publicação: 2022
Outros Autores: Alves, Nuno G., Bártolo, Inês, Fontinha, Diana, Caetano, Soraia, Prudêncio, Miguel, Taveira, Nuno, Melo, Teresa M. V. D. Pinho E
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/58945
Resumo: The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure–activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.
id RCAP_42277b04e40eba12a00095b75e36d7e4
oai_identifier_str oai:repositorio.ul.pt:10451/58945
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoatesspiro-penicillanatesβ-Lactamsspirocyclic compoundsspiro-β-lactamsallenoatesanti-HIVantiplasmodial activitiesphosphane-catalyzed annulationsThe molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure–activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.The authors thank Coimbra Chemistry Centre (CQC), supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through projects UIDB/00313/2020 and UIDP/00313/2020, co-funded by COMPETE2020-UE. iMed. ULisboa, Faculdade de Farmácia de Lisboa, Portugal, is supported by FCT through projects UIDB/04138/2020 and UIDP/04138/2020, cofounded by COMPETE2020-UE. MP acknowledges FCT for grant PTDC/SAU-INF/29550/2017. AA thanks FCT for fellowships SFRH/BD/128910/2017 and COVID/BD/152144/2022. IB is supported by FCT through Norma Transitória-DL57/2016/CP1376/CT0012. The authors also acknowledge the UC-NMR facility for obtaining the NMR data (www.nmrccc.uc.pt).FrontiersRepositório da Universidade de LisboaAlves, AméricoAlves, Nuno G.Bártolo, InêsFontinha, DianaCaetano, SoraiaPrudêncio, MiguelTaveira, NunoMelo, Teresa M. V. D. Pinho E2023-08-21T15:07:38Z2022-10-072023-02-03T12:09:07Z2022-10-07T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/58945engAlves AJS, Alves NG, Bártolo I, Fontinha D, Caetano S, Prudêncio M, et al. Unveiling a family of spiro-β-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates. Front Chem [Internet]. 7 de outubro de 2022;10:1017250. Disponível em: https://www.frontiersin.org/articles/10.3389/fchem.2022.1017250/full2296-2646cv-prod-309187310.3389/fchem.2022.1017250info: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:RCAAP2023-11-08T17:03:32Zoai:repositorio.ul.pt:10451/58945Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:06:41.102303Repositório 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 Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
title Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
spellingShingle Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
Alves, Américo
spiro-penicillanates
β-Lactams
spirocyclic compounds
spiro-β-lactams
allenoates
anti-HIV
antiplasmodial activities
phosphane-catalyzed annulations
title_short Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
title_full Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
title_fullStr Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
title_full_unstemmed Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
title_sort Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates
author Alves, Américo
author_facet Alves, Américo
Alves, Nuno G.
Bártolo, Inês
Fontinha, Diana
Caetano, Soraia
Prudêncio, Miguel
Taveira, Nuno
Melo, Teresa M. V. D. Pinho E
author_role author
author2 Alves, Nuno G.
Bártolo, Inês
Fontinha, Diana
Caetano, Soraia
Prudêncio, Miguel
Taveira, Nuno
Melo, Teresa M. V. D. Pinho E
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Alves, Américo
Alves, Nuno G.
Bártolo, Inês
Fontinha, Diana
Caetano, Soraia
Prudêncio, Miguel
Taveira, Nuno
Melo, Teresa M. V. D. Pinho E
dc.subject.por.fl_str_mv spiro-penicillanates
β-Lactams
spirocyclic compounds
spiro-β-lactams
allenoates
anti-HIV
antiplasmodial activities
phosphane-catalyzed annulations
topic spiro-penicillanates
β-Lactams
spirocyclic compounds
spiro-β-lactams
allenoates
anti-HIV
antiplasmodial activities
phosphane-catalyzed annulations
description The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure–activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.
publishDate 2022
dc.date.none.fl_str_mv 2022-10-07
2022-10-07T00:00:00Z
2023-08-21T15:07:38Z
2023-02-03T12:09:07Z
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/10451/58945
url http://hdl.handle.net/10451/58945
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Alves AJS, Alves NG, Bártolo I, Fontinha D, Caetano S, Prudêncio M, et al. Unveiling a family of spiro-β-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates. Front Chem [Internet]. 7 de outubro de 2022;10:1017250. Disponível em: https://www.frontiersin.org/articles/10.3389/fchem.2022.1017250/full
2296-2646
cv-prod-3091873
10.3389/fchem.2022.1017250
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 Frontiers
publisher.none.fl_str_mv Frontiers
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
repository.mail.fl_str_mv
_version_ 1799134620007006208

Registros relacionados