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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

2022-10-07Journal article Open access
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dc.contributor.authorAlves, Américo
dc.contributor.authorAlves, Nuno G.
dc.contributor.authorBártolo, Inês
dc.contributor.authorFontinha, Diana
dc.contributor.authorCaetano, Soraia
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorTaveira, Nuno
dc.contributor.authorMelo, Teresa M. V. D. Pinho E
dc.date.accessioned2023-08-21T15:07:38Z
dc.date.available2023-08-21T15:07:38Z
dc.date.issued2022-10-07
dc.date.updated2023-02-03T12:09:07Z
dc.description.abstractThe 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.pt_PT
dc.description.sponsorshipThe 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).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAlves 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/fullpt_PT
dc.identifier.doi10.3389/fchem.2022.1017250pt_PT
dc.identifier.issn2296-2646
dc.identifier.slugcv-prod-3091873
dc.identifier.urihttp://hdl.handle.net/10451/58945
dc.language.isoengpt_PT
dc.publisherFrontierspt_PT
dc.relationCoimbra Chemistry Center
dc.relationCoimbra Chemistry Center
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationEnabling strategies for enhanced whole-sporozoite malaria vaccines
dc.relationNovel spiro-lactams as new antimicrobial agents
dc.relationNovel spiro-lactams as new antimicrobial agents
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fchem.2022.1017250/fullpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectspiro-penicillanatespt_PT
dc.subjectβ-Lactamspt_PT
dc.subjectspirocyclic compoundspt_PT
dc.subjectspiro-β-lactamspt_PT
dc.subjectallenoatespt_PT
dc.subjectanti-HIVpt_PT
dc.subjectantiplasmodial activitiespt_PT
dc.subjectphosphane-catalyzed annulationspt_PT
dc.titleUnveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoatespt_PT
dc.typejournal article
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oaire.awardTitleCoimbra Chemistry Center
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oaire.awardTitleResearch Institute for Medicines
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oaire.awardTitleEnabling strategies for enhanced whole-sporozoite malaria vaccines
oaire.awardTitleNovel spiro-lactams as new antimicrobial agents
oaire.awardTitleNovel spiro-lactams as new antimicrobial agents
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oaire.citation.titleFrontiers in Chemistrypt_PT
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