Publicação
Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites
| Resumo: | Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro. |
|---|---|
| Autores principais: | Pereira, Nuno A. L. |
| Outros Autores: | Monteiro, Ângelo; Machado, Marta; Gut, Jiri; Molins, Elies; Perry, Maria Jesus; Dourado, Jorge; Moreira, Rui; Rosenthal, Philip J.; Prudêncio, Miguel; Santos, Maria M. M. |
| Assunto: | Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| Ano: | 2015 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1866810759621640192 |
|---|---|
| author | Pereira, Nuno A. L. |
| author2 | Monteiro, Ângelo Machado, Marta Gut, Jiri Molins, Elies Perry, Maria Jesus Dourado, Jorge Moreira, Rui Rosenthal, Philip J. Prudêncio, Miguel Santos, Maria M. M. |
| author2_role | author author author author author author author author author author |
| author_facet | Pereira, Nuno A. L. Monteiro, Ângelo Machado, Marta Gut, Jiri Molins, Elies Perry, Maria Jesus Dourado, Jorge Moreira, Rui Rosenthal, Philip J. Prudêncio, Miguel Santos, Maria M. M. |
| author_role | author |
| contributor_name_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Pereira, Nuno A. L.\"},{\"Person.name\":\"Monteiro, Ângelo\",\"Person.identifier.orcid\":\"0000-0002-3262-4374\"},{\"Person.name\":\"Machado, Marta\"},{\"Person.name\":\"Gut, Jiri\"},{\"Person.name\":\"Molins, Elies\"},{\"Person.name\":\"Perry, Maria Jesus\",\"Person.identifier.orcid\":\"0000-0002-8110-2740\"},{\"Person.name\":\"Dourado, Jorge\"},{\"Person.name\":\"Moreira, Rui\",\"Person.identifier.orcid\":\"0000-0003-0727-9852\"},{\"Person.name\":\"Rosenthal, Philip J.\"},{\"Person.name\":\"Prudêncio, Miguel\",\"Person.identifier.orcid\":\"0000-0003-1746-6029\"},{\"Person.name\":\"Santos, Maria M. M.\",\"Person.identifier.orcid\":\"0000-0002-2239-9353\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Pereira, Nuno A. L. Monteiro, Ângelo Machado, Marta Gut, Jiri Molins, Elies Perry, Maria Jesus Dourado, Jorge Moreira, Rui Rosenthal, Philip J. Prudêncio, Miguel Santos, Maria M. M. |
| datacite.date.Accepted.fl_str_mv | 2015-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2022-02-11T16:01:53Z |
| datacite.date.embargoed.fl_str_mv | 2022-02-11T16:01:53Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| datacite.subjects.subject.fl_str_mv | Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| datacite.titles.title.fl_str_mv | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| dc.contributor.none.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Pereira, Nuno A. L. Monteiro, Ângelo Machado, Marta Gut, Jiri Molins, Elies Perry, Maria Jesus Dourado, Jorge Moreira, Rui Rosenthal, Philip J. Prudêncio, Miguel Santos, Maria M. M. |
| dc.date.Accepted.fl_str_mv | 2015-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2022-02-11T16:01:53Z |
| dc.date.embargoed.fl_str_mv | 2022-02-11T16:01:53Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/51232 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | Wiley |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| dc.subject.none.fl_str_mv | Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| dc.title.fl_str_mv | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro. |
| dirty | 0 |
| eu_rights_str_mv | restrictedAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/08e2543d-deec-418a-9588-032990f684a5/download |
| funding.funder.alternateName_str_mv | FCT FCT |
| funding.funder.identifier_str_mv | http://doi.org/10.13039/501100001871 http://doi.org/10.13039/501100001871 |
| funding.funder.name_str_mv | Fundação para a Ciência e a Tecnologia Fundação para a Ciência e a Tecnologia |
| funding.name_str_mv | 3599-PPCDT 3599-PPCDT |
| id | ul_85d0d2e7e7e232dc6f4dda523de7a4a7 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/51232 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10451/51232 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Pereira, Nuno A. L. Monteiro, Ângelo Monteiro, Ângelo http://orcid.org/0000-0002-3262-4374 0000-0002-3262-4374 Machado, Marta Gut, Jiri Molins, Elies Perry, Maria Jesus Perry, Maria Jesus https://www.ciencia-id.pt/A516-1A46-D715 A516-1A46-D715 http://orcid.org/0000-0002-8110-2740 0000-0002-8110-2740 Dourado, Jorge Moreira, Rui Moreira, Rui https://www.ciencia-id.pt/8B11-E8C0-DFD0 8B11-E8C0-DFD0 http://orcid.org/0000-0003-0727-9852 0000-0003-0727-9852 Rosenthal, Philip J. Prudêncio, Miguel Prudêncio, Miguel https://www.ciencia-id.pt/5511-16ED-48E0 5511-16ED-48E0 http://orcid.org/0000-0003-1746-6029 0000-0003-1746-6029 Santos, Maria M. M. Santos, Maria M. M. https://www.ciencia-id.pt/5910-2BF6-5F65 5910-2BF6-5F65 http://orcid.org/0000-0002-2239-9353 0000-0002-2239-9353 |
| publishDate | 2015 |
| publisher.none.fl_str_mv | Wiley |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engWileypt_PTMalaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.application/pdfpt_PTEnantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasitesPereira, Nuno A. L.PersonalMonteiro, ÂngeloDSpacehttp://dspace.org/items/0165a0df-71b9-4b11-89cd-27187b1289a7DSpacehttp://dspace.org/items/0165a0df-71b9-4b11-89cd-27187b1289a7MonteiroÂngeloORCIDhttp://orcid.org0000-0002-3262-4374Machado, MartaGut, JiriMolins, EliesPersonalPerry, Maria JesusDSpacehttp://dspace.org/items/710e88bf-5294-4176-ab7c-784fc8717e90DSpacehttp://dspace.org/items/710e88bf-5294-4176-ab7c-784fc8717e90PerryMaria JesusCiência IDhttps://www.ciencia-id.ptA516-1A46-D715ORCIDhttp://orcid.org0000-0002-8110-2740Researcher IDhttps://www.researcherid.comE-1746-2015Scopus Author IDhttps://www.scopus.com55254669000Dourado, JorgePersonalMoreira, RuiDSpacehttp://dspace.org/items/7a2ba2a9-2433-4055-9264-bc3164c6cd0dDSpacehttp://dspace.org/items/7a2ba2a9-2433-4055-9264-bc3164c6cd0dMoreiraRuiCiência IDhttps://www.ciencia-id.pt8B11-E8C0-DFD0ORCIDhttp://orcid.org0000-0003-0727-9852Scopus Author IDhttps://www.scopus.com7102554088Rosenthal, Philip J.PersonalPrudêncio, MiguelDSpacehttp://dspace.org/items/80e4e74d-bf34-4a71-8530-cc3280543b65DSpacehttp://dspace.org/items/80e4e74d-bf34-4a71-8530-cc3280543b65PrudêncioMiguelCiência IDhttps://www.ciencia-id.pt5511-16ED-48E0ORCIDhttp://orcid.org0000-0003-1746-6029Scopus Author IDhttps://www.scopus.com6603561872PersonalSantos, Maria M. M.DSpacehttp://dspace.org/items/07fcf050-9273-4a16-9053-47d46229729aDSpacehttp://dspace.org/items/07fcf050-9273-4a16-9053-47d46229729aSantosMariaCiência IDhttps://www.ciencia-id.pt5910-2BF6-5F65ORCIDhttp://orcid.org0000-0002-2239-9353Researcher IDhttps://www.researcherid.comI-7189-2013Scopus Author IDhttps://www.scopus.com8634544500Scopus Author IDhttps://www.scopus.com57200135931HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptISSNIsPartOf1860-7179DOIIsPartOf10.1002/cmdc.2015004292022-02-11T16:01:53Z20152015-01-01T00:00:00ZHandlehttp://hdl.handle.net/10451/51232http://purl.org/coar/access_right/c_16ecrestricted accessDiastereoselectivityDrug designDual-stage antimalarialsMalariaNitrogen heterocycles1703642 bytesFundação para a Ciência e a TecnologiaEnantioselective synthesis of indole alkaloids and their application as NMDA antagonists3599-PPCDTCrossref Funder IDhttp://doi.org/10.13039/501100001871Fundação para a Ciência e a TecnologiaUtilization of host cell resources by the malaria parasite in the liver3599-PPCDTCrossref Funder IDhttp://doi.org/10.13039/501100001871literaturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_16ecapplication/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/08e2543d-deec-418a-9588-032990f684a5/downloadChemMedChem101220802089 |
| spellingShingle | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites Pereira, Nuno A. L. Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| status | SINGLETON |
| subject.fl_str_mv | Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| title | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| title_full | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| title_fullStr | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| title_full_unstemmed | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| title_short | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| title_sort | Enantiopure Indolizinoindolones with in vitro activity against blood- and liver-stage malaria parasites |
| topic | Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| topic_facet | Diastereoselectivity Drug design Dual-stage antimalarials Malaria Nitrogen heterocycles |
| url | http://hdl.handle.net/10451/51232 |
| visible | 1 |