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Reinvestigating old pharmacophores: are 4-Aminoquinolines and Tetraoxanes potential two-stage antimalarials?

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dc.contributor.authorTerzić, Natasa
dc.contributor.authorKonstantinović, Jelena
dc.contributor.authorTot, Mikloš
dc.contributor.authorBurojević, Jovana
dc.contributor.authorDjurković-Djaković, Olgica
dc.contributor.authorSrbljanović, Jelena
dc.contributor.authorŠtajner, Tijana
dc.contributor.authorVerbić, Tatjana
dc.contributor.authorZlatović, Mario
dc.contributor.authorMachado, Marta
dc.contributor.authorAlbuquerque, Inês S.
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorSciotti, Richard J.
dc.contributor.authorPecic, Stevan
dc.contributor.authorD’Alessandro, Sarah
dc.contributor.authorTaramelli, Donatella
dc.contributor.authorŠolaja, Bogdan A.
dc.date.accessioned2022-03-07T16:54:54Z
dc.date.available2022-03-07T16:54:54Z
dc.date.issued2015
dc.description© 2015 American Chemical Societypt_PT
dc.description.abstractThe syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.pt_PT
dc.description.sponsorshipThis research was supported by The Ministry of Science and Technological Development of Serbia (grant nos. 172008 and 41019), the Serbian Academy of Sciences and Arts, Fundação para a Ciência e Tecnologia, Portugal (grant PTDC/SAU-MIC/117060/2010), the Bill & Melinda Gates Foundation (grant OPP1040394).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Med Chem. 2016 Jan 14;59(1):264-281pt_PT
dc.identifier.doi10.1021/acs.jmedchem.5b01374pt_PT
dc.identifier.eissn1520-4804
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/10451/51639
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.relationUtilization of host cell resources by the malaria parasite in the liver
dc.relation.publisherversionhttps://pubs.acs.org/journal/jmcmarpt_PT
dc.titleReinvestigating old pharmacophores: are 4-Aminoquinolines and Tetraoxanes potential two-stage antimalarials?pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberPTDC/SAU-MIC/117060/2010
oaire.awardTitleUtilization of host cell resources by the malaria parasite in the liver
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-MIC%2F117060%2F2010/PT
oaire.citation.endPage281pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage264pt_PT
oaire.citation.titleJournal of Medicinal Chemistrypt_PT
oaire.citation.volume59pt_PT
oaire.fundingStream3599-PPCDT
person.familyNameS. Albuquerque
person.familyNamePrudêncio
person.givenNameInês
person.givenNameMiguel
person.identifierhttps://scholar.google.pt/citations?user=zduN6wsAAAAJ&hl=pt-PT&oi=ao
person.identifier.ciencia-idAA13-20AA-F50C
person.identifier.ciencia-id5511-16ED-48E0
person.identifier.orcid0000-0002-1108-0961
person.identifier.orcid0000-0003-1746-6029
person.identifier.ridP-5325-2016
person.identifier.scopus-author-id6603561872
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication37a8c939-e874-41d7-86bd-9d6d349467e4
relation.isAuthorOfPublication80e4e74d-bf34-4a71-8530-cc3280543b65
relation.isAuthorOfPublication.latestForDiscovery37a8c939-e874-41d7-86bd-9d6d349467e4
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