Activity of N-lutidinylarylcarboxamides against Leishmania donovani and L.braziliensis
Three arylcarboxamides issued from 2-amino- 4,6-dimethylpyridine, benzamide 1, furan-2-carboxamide 2 and 5-bromofuran-2-carboxamide 3 were evaluated against Leishmania promastigotes, at three doses, 0.5, 5, and 50 µM. Although benzamide 1 exerted but a moderate inhibition against cultured extracellular promastigotes at a concentration of 50 µM, furan-2-carboxamides 2 and 3 had potent activity at the same concentration. The IC₅₀ of 2 against L. donovani and L. braziliensis were 29.9 and 28.3 µM and those of 3 were 25.9 and 36.6 µM, respectively. In a BALB/c mice model of visceral leishmaniosis, an intraperitoneal administration of 10 mg/kg of 2, for 5 days, led to a consistent parasite burden reduction in the spleen smears (75.8 ± 5.7%) and in the microdilution spleen cultures (72.1 ± 0.6%). A very significant correlation (r = 0.96) was found between the two methods of spleen parasite burden quantification. These amides also exhibit potent antiinflammatory activity and it was previously stated that they inhibit arachidonic acid production by interfering in the PLA₂ activation. This suggests fact that they could disrupt Leishmania membrane lipid integrity by protein kinase C inhibition.
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