Conjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorGEHRKE, Sebastian S.
dc.contributor.authorPINTO, Erika G.
dc.contributor.authorSTEVERDING, Dietmar
dc.contributor.authorPLEBAN, Karin
dc.contributor.authorTEMPONE, Andre G.
dc.contributor.authorHIDER, Robert C.
dc.contributor.authorWAGNER, Gerd K.
dc.date.accessioned2013-09-23T17:03:52Z
dc.date.available2013-09-23T17:03:52Z
dc.date.issued2013
dc.description.abstractIron is an essential growth component in all living organisms and plays a central role in numerous biochemical processes due to its redox potential and high affinity for oxygen. The use of iron chelators has been suggested as a novel therapeutic approach towards parasitic infections, such as malaria, sleeping sickness and leishmaniasis. Known iron chelating agents such as Deferoxamine and the 3-hydroxypyridin-4-one (HPO) Deferiprone possess anti-parasitic activity but suffer from mammalian toxicity, relatively modest potency, and/or poor oral availability. In this study, we have developed novel derivatives of Deferiprone with increased anti-parasitic activity and reduced cytotoxicity against human cell lines. Of particular interest are several new derivatives in which the HPO scaffold has been conjugated, via a linker, to the 4-aminoquinoline ring system present in the known anti-malaria drug Chloroquine. We report the inhibitory activity of these novel analogues against four parasitic protozoa, Trypanosoma brucei, Trypanosoma cruzi, Leishmania infantum and Plasmodium falciparum, and, for direct comparison, against human cells lines. We also present data, which support the hypothesis that iron starvation is the major cause of growth inhibition of these new Deferiprone-Chloroquine conjugates in T. brucei.
dc.description.indexMEDLINE
dc.description.sponsorshipNorwich Research Park
dc.description.sponsorshipKing's College London (King's Brazil Initiative)
dc.description.sponsorshipFAPESP Sao Paulo [2011/50577-7]
dc.identifier.citationBIOORGANIC & MEDICINAL CHEMISTRY, v.21, n.3, p.805-813, 2013
dc.identifier.doi10.1016/j.bmc.2012.11.009
dc.identifier.issn0968-0896
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/2471
dc.language.isoeng
dc.publisherPERGAMON-ELSEVIER SCIENCE LTD
dc.relation.ispartofBioorganic & Medicinal Chemistry
dc.rightsrestrictedAccess
dc.rights.holderCopyright PERGAMON-ELSEVIER SCIENCE LTD
dc.subjectIron chelator
dc.subjectAnti-parasitic
dc.subjectTrypanosoma
dc.subjectHybrid drugs
dc.subjectDeferiprone
dc.subject.otherplasmodium-falciparum
dc.subject.otherantimalarial activity
dc.subject.otherantiplasmodial activity
dc.subject.otherbiological evaluation
dc.subject.othertrypanosoma-brucei
dc.subject.otherchagas-disease
dc.subject.otherhost iron
dc.subject.otherleishmania
dc.subject.otherinhibition
dc.subject.otherchloroquine
dc.subject.wosBiochemistry & Molecular Biology
dc.subject.wosChemistry, Medicinal
dc.subject.wosChemistry, Organic
dc.titleConjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countryisogb
hcfmusp.author.externalGEHRKE, Sebastian S.:Kings Coll London, Inst Pharmaceut Sci, Sch Biomed Sci, London SE1 9NH, England; Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England; Univ E Anglia, Biomed Res Ctr, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England
hcfmusp.author.externalSTEVERDING, Dietmar:Univ E Anglia, Biomed Res Ctr, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England
hcfmusp.author.externalPLEBAN, Karin:Kings Coll London, Inst Pharmaceut Sci, Sch Biomed Sci, London SE1 9NH, England
hcfmusp.author.externalTEMPONE, Andre G.:Adolfo Lutz Inst, Dept Parasitol, Sao Paulo, Brazil
hcfmusp.author.externalHIDER, Robert C.:Kings Coll London, Inst Pharmaceut Sci, Sch Biomed Sci, London SE1 9NH, England
hcfmusp.author.externalWAGNER, Gerd K.:Kings Coll London, Inst Pharmaceut Sci, Sch Biomed Sci, London SE1 9NH, England; Kings Coll London, Dept Chem, Sch Biomed Sci, London SE1 9NH, England
hcfmusp.citation.scopus27
hcfmusp.contributor.author-fmusphcERIKA GRACIELLE PINTO
hcfmusp.description.beginpage805
hcfmusp.description.endpage813
hcfmusp.description.issue3
hcfmusp.description.volume21
hcfmusp.origemWOS
hcfmusp.origem.pubmed23266185
hcfmusp.origem.scopus2-s2.0-84872296730
hcfmusp.origem.wosWOS:000313696900023
hcfmusp.publisher.cityOXFORD
hcfmusp.publisher.countryENGLAND
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