Publication
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action
| dc.contributor.author | Mendes, Andreia | |
| dc.contributor.author | Armada, Ana | |
| dc.contributor.author | Cabral, Lília | |
| dc.contributor.author | Amado, Patrícia | |
| dc.contributor.author | Campino, Lenea | |
| dc.contributor.author | Cristiano, Maria de Lurdes | |
| dc.contributor.author | Cortes, Sofia | |
| dc.date.accessioned | 2022-04-22T13:35:29Z | |
| dc.date.available | 2022-04-22T13:35:29Z | |
| dc.date.issued | 2022-04-03 | |
| dc.date.updated | 2022-04-21T21:04:01Z | |
| dc.description.abstract | Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on <i>Leishmania</i> parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against <i>L. infantum</i> and <i>L. donovani</i> and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 <i>Leishmania</i> species, with IC<sub>50</sub> values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on <i>L. infantum</i> amastigotes (IC<sub>50</sub> 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes. | pt_PT |
| dc.description.sponsorship | UID/MULTI/04326/2021; UI0313B/QUI/2020 | |
| dc.description.version | info:eu-repo/semantics/publishedVersion | pt_PT |
| dc.identifier.citation | Pharmaceuticals 15 (4): 446 (2022) | pt_PT |
| dc.identifier.doi | 10.3390/ph15040446 | pt_PT |
| dc.identifier.issn | doi: 10.3390/ph15040446 | |
| dc.identifier.issn | 1424-8247 | |
| dc.identifier.uri | http://hdl.handle.net/10400.1/17777 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | MDPI | pt_PT |
| dc.relation | Global Health and Tropical Medicine | |
| dc.relation | A Chemical Proteomics Approach to Defining the Mechanism of Artemisinin Action and Resistance in PfK13 Resistant parasites | |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.subject | Leishmania infantum | pt_PT |
| dc.subject | Leishmania donovani | pt_PT |
| dc.subject | Leishmaniasis | pt_PT |
| dc.subject | 1,2,4-trioxolanes | pt_PT |
| dc.subject | 1,2,4,5-tetraoxanes | pt_PT |
| dc.subject | Selectivity | pt_PT |
| dc.subject | Mode of action | pt_PT |
| dc.subject | Reactive oxygen species | pt_PT |
| dc.title | 1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Global Health and Tropical Medicine | |
| oaire.awardTitle | A Chemical Proteomics Approach to Defining the Mechanism of Artemisinin Action and Resistance in PfK13 Resistant parasites | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00743%2F2015%2FCP1320%2FCT0001/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04413%2F2020/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F130407%2F2017/PT | |
| oaire.citation.issue | 4 | pt_PT |
| oaire.citation.startPage | 446 | pt_PT |
| oaire.citation.title | Pharmaceuticals | pt_PT |
| oaire.citation.volume | 15 | pt_PT |
| oaire.fundingStream | Investigador FCT | |
| oaire.fundingStream | 6817 - DCRRNI ID | |
| person.familyName | Cabral | |
| person.familyName | Menalha Amado | |
| person.familyName | Cristiano | |
| person.givenName | Lília | |
| person.givenName | Patrícia Sofia | |
| person.givenName | Maria de Lurdes | |
| person.identifier.ciencia-id | 3510-24A8-36B6 | |
| person.identifier.ciencia-id | 8617-A360-B70A | |
| person.identifier.ciencia-id | E411-6006-5A01 | |
| person.identifier.orcid | 0000-0001-9362-8128 | |
| person.identifier.orcid | 0000-0002-7307-9210 | |
| 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.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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