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On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

2017-06Journal article Open access
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dc.contributor.authorHorta, Pedro
dc.contributor.authorHenriques, Marta S. C.
dc.contributor.authorBras, Elisa M.
dc.contributor.authorMurtinheira, Fernanda
dc.contributor.authorNogueira, Fatima
dc.contributor.authorO'Neill, Paul M.
dc.contributor.authorPaixao, Jose A.
dc.contributor.authorFausto, Rui
dc.contributor.authorCristiano, Maria De Lurdes
dc.date.accessioned2018-12-07T14:53:28Z
dc.date.available2018-12-07T14:53:28Z
dc.date.issued2017-06
dc.description.abstractRecent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
dc.description.sponsorshipFundacao para a Ciencia e Tecnologia (FCT - Portugal) [UID/Multi/04326/2013]; QREN-COMPETE-UE; CCMAR; FCT [SFRH/BD/81821/2011, RECI/BBB-BQB/0230/2012, UI0313/QUI/2013, UID/FIS/04564/2016]; FEDER/COMPETE-UE; [PTDC/QEQ-QFI/3284/2014 - POCI-01-0145-FEDER-016617]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1515/pac-2016-1119
dc.identifier.issn0033-4545
dc.identifier.issn1365-3075
dc.identifier.urihttp://hdl.handle.net/10400.1/11533
dc.language.isoeng
dc.peerreviewedyes
dc.publisherWalter De Gruyter Gmbh
dc.relationNMR Net - National Facility for Nuclear Magnetic Resonance: from Molecular Structure and Dynamics to Protein Function, Cell Physiology, and Metabolomics
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectGaussian-basis sets
dc.subjectPlasmodium-Falciparum
dc.subjectMolecular calculations
dc.subjectAb-Initio
dc.subjectRotational-Isomerism
dc.subjectDensity
dc.subjectComplex
dc.subjectFormate
dc.subjectAgents
dc.subjectAtoms
dc.titleOn the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNMR Net - National Facility for Nuclear Magnetic Resonance: from Molecular Structure and Dynamics to Protein Function, Cell Physiology, and Metabolomics
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04326%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F81821%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/RECI%2FBBB-BQB%2F0230%2F2012/PT
oaire.citation.endPage780
oaire.citation.issue6
oaire.citation.startPage765
oaire.citation.titlePure and Applied Chemistry
oaire.citation.volume89
oaire.fundingStream5876
oaire.fundingStreamSFRH
oaire.fundingStream3599-PPCDT
person.familyNameHorta
person.familyNameCristiano
person.givenNamePedro
person.givenNameMaria de Lurdes
person.identifier.ciencia-idFA1A-E8E4-9C24
person.identifier.ciencia-idE411-6006-5A01
person.identifier.orcid0000-0001-7313-338X
person.identifier.orcid0000-0002-9447-2855
person.identifier.ridG-2345-2012
person.identifier.scopus-author-id9238724800
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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