{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:04:00Z","timestamp":1790633040158,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,4,3]],"date-time":"2022-04-03T00:00:00Z","timestamp":1648944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UID\/MULTI\/04326\/2021 (CCMAR"],"award-info":[{"award-number":["UID\/MULTI\/04326\/2021 (CCMAR"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UID\/Multi\/04413\/2019 (GHTM)"],"award-info":[{"award-number":["UID\/Multi\/04413\/2019 (GHTM)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UI0313B\/QUI\/2020 (CQC)"],"award-info":[{"award-number":["UI0313B\/QUI\/2020 (CQC)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["IF\/00743\/2015\/CP1320"],"award-info":[{"award-number":["IF\/00743\/2015\/CP1320"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/130407\/2017 (PSMA)"],"award-info":[{"award-number":["SFRH\/BD\/130407\/2017 (PSMA)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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 Leishmania parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against L. infantum and L. donovani 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 Leishmania species, with IC50 values ranging from 13.0 \u00b1 1.7 \u00b5M to 793.0 \u00b1 37.2 \u00b5M. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on L. infantum amastigotes (IC50 13.2 \u00b1 5.2 and 23.9 \u00b1 2.7 \u00b5M) 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.<\/jats:p>","DOI":"10.3390\/ph15040446","type":"journal-article","created":{"date-parts":[[2022,4,3]],"date-time":"2022-04-03T06:04:01Z","timestamp":1648965841000},"page":"446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["1,2,4-Trioxolane and 1,2,4,5-Tetraoxane Endoperoxides against Old-World Leishmania Parasites: In Vitro Activity and Mode of Action"],"prefix":"10.3390","volume":"15","author":[{"given":"Andreia","family":"Mendes","sequence":"first","affiliation":[{"name":"Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira, 100, 1349-008 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Armada","sequence":"additional","affiliation":[{"name":"Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira, 100, 1349-008 Lisboa, Portugal"},{"name":"Global Health Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira, 100, 1349-008 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00edlia I. L.","family":"Cabral","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"},{"name":"Departamento de Qu\u00edmica e Farm\u00e1cia, Faculdade de Ci\u00eancias e Tecnologia, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7307-9210","authenticated-orcid":false,"given":"Patr\u00edcia S. M.","family":"Amado","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"},{"name":"Departamento de Qu\u00edmica e Farm\u00e1cia, Faculdade de Ci\u00eancias e Tecnologia, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenea","family":"Campino","sequence":"additional","affiliation":[{"name":"Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira, 100, 1349-008 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9447-2855","authenticated-orcid":false,"given":"Maria L. S.","family":"Cristiano","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"},{"name":"Departamento de Qu\u00edmica e Farm\u00e1cia, Faculdade de Ci\u00eancias e Tecnologia, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5850-6950","authenticated-orcid":false,"given":"Sofia","family":"Cortes","sequence":"additional","affiliation":[{"name":"Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira, 100, 1349-008 Lisboa, Portugal"},{"name":"Global Health Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira, 100, 1349-008 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,3]]},"reference":[{"key":"ref_1","unstructured":"(2021, November 15). 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