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Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies

2021Journal article Restricted access
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dc.contributor.authorWoodley, Christopher M.
dc.contributor.authorAmado, Patrícia
dc.contributor.authorCristiano, Maria De Lurdes
dc.contributor.authorO'Neill, Paul M.
dc.date.accessioned2021-09-22T09:35:00Z
dc.date.available2021-09-22T09:35:00Z
dc.date.issued2021
dc.description.abstractArtemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-trioxolanes (arterolane and artefenomel) and the 1,2,4,5-tetraoxanes (N205 and E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2-dioxane, Arteflene, and 1,2,4-trioxanes fenozan-50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.pt_PT
dc.description.sponsorshipSFRH/BD/130407/2017; UID/MULTI/04326/2020pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1002/med.21849pt_PT
dc.identifier.eissn1098-1128
dc.identifier.urihttp://hdl.handle.net/10400.1/17140
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationAlgarve Centre for Marine Sciences
dc.subjectAntimalarialpt_PT
dc.subjectArtemisininpt_PT
dc.subjectEndoperoxidept_PT
dc.subjectMalariapt_PT
dc.subjectPlasmodium falciparumpt_PT
dc.titleArtemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studiespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04326%2F2020/PT
oaire.citation.titleMedicinal Research Reviewspt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameMenalha Amado
person.familyNameCristiano
person.givenNamePatrícia Sofia
person.givenNameMaria de Lurdes
person.identifier.ciencia-id8617-A360-B70A
person.identifier.ciencia-idE411-6006-5A01
person.identifier.orcid0000-0002-7307-9210
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.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublicationb16751a6-748e-44b0-9c59-058cbd5b2cc3
relation.isAuthorOfPublication.latestForDiscovery5b28f1eb-1d56-4094-8242-2d1163618e5f
relation.isProjectOfPublicationfafa76a6-2cd2-4a6d-a3c9-772f34d3b91f
relation.isProjectOfPublication.latestForDiscoveryfafa76a6-2cd2-4a6d-a3c9-772f34d3b91f

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