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Molecules 2018, 23(4), 864; https://doi.org/10.3390/molecules23040864

Antileishmanial Activity of 2-Methoxy-4H-spiro-[naphthalene-1,2′-oxiran]-4-one (Epoxymethoxy-lawsone): A Promising New Drug Candidate for Leishmaniasis Treatment

1
Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz-Fundação Oswaldo Cruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, Brasil
2
Laboratório de Imunoparasitologia, Instituto Oswaldo Cruz-Fundação Oswaldo Cruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, Brasil
3
Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz-Fundação Oswaldo Cruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, Brasil
4
Laboratório de Imunologia Clínica, Instituto Oswaldo Cruz-Fundação Oswaldo Cruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, Brasil
5
Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz-Fundação Oswaldo Cruz, Avenida Brasil 4365, Rio de Janeiro 21040-900, RJ, Brasil
6
Laboratório de Interação Celular e Molecular-LICEM, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
7
Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Niterói 24241-002, RJ, Brasil
*
Author to whom correspondence should be addressed.
Received: 7 March 2018 / Revised: 3 April 2018 / Accepted: 5 April 2018 / Published: 10 April 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Epoxymethoxylawsone is a naphthoquinone derivative promising as drug candidate for the treatment of leishmaniases. In the present work the effectiveness of epoxymethoxylawsone, and meglumine antimoniate on Leishmania (Leishmania) amazonensis parasites and on mice paw lesions of infected BALB/c mice was assessed. In an intracellular amastigotes assay, the half-maximal inhibitory concentration (IC50) value for epoxymethoxylawsone was slightly higher (1.7-fold) than that found for meglumine antimoniate. The efficacy of both drugs became more evident after 48 h of exposure when either the oxirane compound and reference drug reached 18-fold and 7.4-fold lower IC50 values (0.40 ± 0.001 µM and 0.60 ± 0.02 µM), respectively. Promastigotes were also affected by epoxymethoxylawsone after 24 h of incubation (IC50 = 45.45 ± 5.0 µM), but with IC50 6-fold higher than those found for intracellular amastigotes. Cytotoxicity analysis revealed that epoxymethoxylawsone (CC50 = 40.05 ± µM) has 1.7-fold higher effects than meglumine antimoniate (CC50 = 24.14 ± 2.6 µM). Treatment of the paw lesion in infected BALB/c mice with epoxymethoxy-lawsone led to a significant 27% reduction (p < 0.05) of the lesion size, for all administrated doses, compared to the control group. Lesion reduction was also detected after mice treatment with meglumine antimoniate, reaching 31.0% (0.23 mg of Sb(V)/Kg/day and 2.27 mg of Sb(V)/Kg/day) and 64.0% (22.7 mg of Sb(V)/Kg/day). In addition, mice lesion ultrastructural changes were evidenced in amastigotes. The set of data gathered here indicate that epoxymethoxylawsone has pronounced effects on parasites and merits furthering to the preclinical stage. View Full-Text
Keywords: antileishmanial activity; oxiranes; naphthoquinones; epoxymethoxy-lawsone; meglumine antimoniate antileishmanial activity; oxiranes; naphthoquinones; epoxymethoxy-lawsone; meglumine antimoniate
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Oliveira, L.F.G.; Souza-Silva, F.; de Castro Côrtes, L.M.; Cysne-Finkelstein, L.; de Souza Pereira, M.C.; de Oliveira Junior, F.O.; Pinho, R.T.; Corte Real, S.; Bourguignon, S.C.; Ferreira, V.F.; Alves, C.R. Antileishmanial Activity of 2-Methoxy-4H-spiro-[naphthalene-1,2′-oxiran]-4-one (Epoxymethoxy-lawsone): A Promising New Drug Candidate for Leishmaniasis Treatment. Molecules 2018, 23, 864.

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