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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Tempone, Andre Gustavo [1] ; Ferreira, Daiane Dias [1] ; Lima, Marta Lopes [1] ; Costa Silva, Thais Alves [1] ; Borborema, Samanta E. T. [1] ; Reimao, Juliana Quero [2] ; Galuppo, Mariana K. [1] ; Guerra, Juliana Mariotti [1] ; Russell, Angelie J. [3, 4] ; Wynne, Graham M. [3] ; Lai, Roy Y. L. [5] ; Cadelis, Melissa M. [5] ; Copp, Brent R. [5]
Total Authors: 13
[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Ave Dr Arnaldo 351, 8 Andar, BR-01246902 Sao Paulo, SP - Brazil
[2] Fac Med Jundiai, Rua Francisco Telles 250, BR-13202550 Jundiai, SP - Brazil
[3] Univ Oxford, Dept Chem, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA - England
[4] Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford OX1 3QT - England
[5] Univ Auckland, Sch Chem Sci, Private Bag 92019, Auckland 1142 - New Zealand
Total Affiliations: 5
Document type: Journal article
Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 139, p. 947-960, OCT 20 2017.
Web of Science Citations: 16

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, twentyseven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their anti parasitic 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 mu M 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 mu M, 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 longterm treatments in experimental Chagas disease. (C) 2017 Elsevier Masson SAS. All rights reserved. (AU)

FAPESP's process: 13/07275-5 - In vitro study of cellular immune response against synthetic drugs with antileishmanial activities
Grantee:Thaís Alves da Costa Silva
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 15/23403-9 - Rational Pre-Clinical Study of New Drug Candidates Against Neglected Protozoan Diseases Using Pharmacokinetic Approaches
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants
FAPESP's process: 15/50075-2 - Brazilian biodiversity as a source for novel drug scaffolds against neglected protozoan diseases
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants