Publication
New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum
| dc.contributor.author | Lobo, Lis | |
| dc.contributor.author | Cabral, Lília | |
| dc.contributor.author | Sena, Maria I. | |
| dc.contributor.author | Guerreiro, Bruno | |
| dc.contributor.author | Rodrigues, António S. | |
| dc.contributor.author | de Andrade-Neto, Valter F. | |
| dc.contributor.author | Cristiano, Maria Lurdes Santos | |
| dc.contributor.author | Nogueira, Fatima | |
| dc.date.accessioned | 2018-05-03T09:33:38Z | |
| dc.date.available | 2018-05-03T09:33:38Z | |
| dc.date.issued | 2018-04-03 | |
| dc.date.updated | 2018-05-01T04:31:30Z | |
| dc.description.abstract | Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3–71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane–tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice. | pt_PT |
| dc.description.version | info:eu-repo/semantics/publishedVersion | pt_PT |
| dc.identifier.citation | Malaria Journal. 2018 Apr 03;17(1):145 | pt_PT |
| dc.identifier.doi | 10.1186/s12936-018-2281-x | pt_PT |
| dc.identifier.other | AUT: MCR00716; | |
| dc.identifier.uri | http://hdl.handle.net/10400.1/10655 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | BioMed Central | pt_PT |
| dc.rights.holder | The Author(s) | |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.subject | Plasmodium falciparum | pt_PT |
| dc.subject | Trioxolane–tetrazole conjugates | pt_PT |
| dc.subject | Tetraoxane–tetrazole conjugates | pt_PT |
| dc.subject | In vivo antimalarial activity | pt_PT |
| dc.subject | Antimalarial drug resistance | pt_PT |
| dc.title | New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04413%2F2013/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04326%2F2013/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/5876/UID%2FBIM%2F00009%2F2013/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMAR-BIO%2F4132%2F2014/PT | |
| oaire.citation.issue | 1 | pt_PT |
| oaire.citation.startPage | 145 | pt_PT |
| oaire.citation.title | Malaria Journal | pt_PT |
| oaire.citation.volume | 17 | pt_PT |
| oaire.fundingStream | 5876 | |
| oaire.fundingStream | 5876 | |
| oaire.fundingStream | 5876 | |
| oaire.fundingStream | 3599-PPCDT | |
| person.familyName | Cabral | |
| person.familyName | Guerreiro | |
| person.familyName | Cristiano | |
| person.givenName | Lília | |
| person.givenName | Bruno | |
| person.givenName | Maria de Lurdes | |
| person.identifier.ciencia-id | 3510-24A8-36B6 | |
| person.identifier.ciencia-id | 1116-64F6-3D01 | |
| person.identifier.ciencia-id | E411-6006-5A01 | |
| person.identifier.orcid | 0000-0001-9362-8128 | |
| person.identifier.orcid | 0000-0001-7219-7939 | |
| person.identifier.orcid | 0000-0002-9447-2855 | |
| person.identifier.rid | M-4279-2013 | |
| person.identifier.rid | G-2345-2012 | |
| person.identifier.scopus-author-id | 9238724800 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | article | pt_PT |
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