Activity of Naphthylisoquinoline Alkaloids and Synthetic Analogs against Leishmania major

Abstract

The current treatments for leishmaniasis are unsatisfactory due to their toxic side effects, the high costs, and the increasing problems with drug resistance. Thus, there is an urgent need for alternative drugs against leishmaniasis. Different approaches have been used to identify novel pharmacophores against Leishmania sp. parasites and one strategy has been the analysis of naturally occurring plant-derived compounds including naphthylisoquinoline alkaloids. In the present study, we examined the ability of these alkaloids to inhibit the growth of Leishmania major promastigotes and evaluated their effect on macrophages, dendritic cells, and fibroblasts. Furthermore, we determined the efficacy of selected compounds in decreasing the infection rate of macrophages and regulating their production of cytokines and nitric oxide. Our results demonstrate that the naphthylisoquinoline alkaloids ancistrocladiniums A and B (compounds 10 and 11) and the synthetic isoquinolinium salt (compound 14) were effective against intracellular amastigotes in the low sub-micromolar range, while toxicity against mammalian cells was observed at concentrations that were significantly higher than those needed to impair parasite replication. The activities of compounds 11 and 14 were mainly directed against the amastigote stage of L. major. This effect was not associated with the stimulation of host macrophages to produce nitric oxide or secrete cytokines relevant for the leishmanicidal function. In conclusion, our data suggest that ancistrocladiniums A and B (compounds 10 and 11) and the synthetically prepared isoquinolinium salt (compound 14) are promising candidates to be considered as lead compounds for leishmanicidal drugs.