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

Epoxymethoxy-lawsone is a naphthoquinone derivative promising as drug candidate for the treatment of leishmaniases. In the present work the effectiveness of Epoxymethoxy-lawsone, 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 Epoxymethoxy-lawsone 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 mu M and 0.60 +/- 0.02 mu M), respectively. Promastigotes were also affected by Epoxymethoxy-lawsone after 24 h of incubation (IC50 = 45.45 +/- 5.0 mu M), but with IC50 6-fold higher than those found for intracellular amastigotes. Cytotoxicity analysis revealed that Epoxymethoxy-lawsone (CC50 = 40.05 +/- mu M) has 1.7-fold higher effects than meglumine antimoniate (CC50 = 24.14 +/- 2.6 mu M). 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 Epoxymethoxy-lawsone has pronounced effects on parasites and merits furthering to the preclinical stage.