Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi.

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dc.contributor.author Tempone, Andre Gustavo en
dc.contributor.author Tempone, Andre Gustavo en
dc.contributor.author Ferreira, Daiane Dias en
dc.contributor.author Lima, Marta Lopes en
dc.contributor.author Costa Silva, Thais Alves en
dc.contributor.author Borborema, Samanta ET en
dc.contributor.author Reimão, Juliana Quero en
dc.contributor.author Galuppo, Mariana K en
dc.contributor.author Guerra, Juliana Mariotti en
dc.contributor.author Russell, Angelie J en
dc.contributor.author Wynne, Graham M en
dc.contributor.author Lai, Roy YL en
dc.contributor.author Cadelis, Melissa en
dc.contributor.author Copp, Brent en
dc.date.accessioned 2018-11-13T23:48:09Z en
dc.date.issued 2017-10 en
dc.identifier.citation European Journal of Medicinal Chemistry 139:947-960 20 Oct 2017 en
dc.identifier.issn 1768-3254 en
dc.identifier.uri http://hdl.handle.net/2292/44239 en
dc.description.abstract The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 μM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 μM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p < 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as long-term treatments in experimental Chagas disease. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries European journal of medicinal chemistry en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Leishmania infantum en
dc.subject Trypanosoma cruzi en
dc.subject Pyrones en
dc.subject Antiprotozoal Agents en
dc.subject Parasitic Sensitivity Tests en
dc.subject Molecular Structure en
dc.subject Structure-Activity Relationship en
dc.subject Dose-Response Relationship, Drug en
dc.title Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi. en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.ejmech.2017.08.055 en
pubs.begin-page 947 en
pubs.volume 139 en
dc.rights.holder Copyright: Elsevier en
dc.identifier.pmid 28881289 en
pubs.end-page 960 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype Journal Article en
pubs.elements-id 668636 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Molecular Medicine en
pubs.org-id Science en
pubs.org-id Chemistry en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1768-3254 en
pubs.record-created-at-source-date 2017-09-07 en
pubs.dimensions-id 28881289 en

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