ABSTRACT
A series of oxygenated analogues of marine 3-alkylpyridine alkaloids were synthesized, and their leishmanicidal activity was assayed. All compounds were prepared from 3-pyridinepropanol in few steps and in good yields. The key step for the synthesis of these compounds was a classic Williamson etherification under phase-transfer conditions. Besides toxicity in peritoneal macrophages, the compounds exhibited a significant leishmanicidal activity. Of twelve compounds tested, five showed a strong leishmanicidal activity against promastigote forms of Leishmania amazonensis and L. braziliensis with IC50 below 10 µm. Compounds 11, 14, 15, and 16 showed a strong leishmanicidal activity on intracellular amastigotes (IC50 values of 2.78; 0.27; 1.03, and 1.33 µm, respectively), which is unlikely to be owing to the activation of nitric oxide production by macrophages.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Leishmania/drug effects , Alkaloids/toxicity , Animals , Antiprotozoal Agents/toxicity , Cells, Cultured , Humans , Inhibitory Concentration 50 , Leishmaniasis/drug therapy , Macrophages/drug effects , Macrophages/metabolism , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Nitric Oxide/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/toxicityABSTRACT
A series of new oxygenated analogues of marine 3-alkylpyridine alkaloids were prepared from 3-pyridinepropanol in few steps and in good yields. The key step for the synthesis of these compounds was a Williamson etherification under phase-transfer conditions. All new compounds were evaluated for their antiplasmodial activity and cytotoxicity. A significant reduction in parasitaemia was observed for some of the prepared compounds, and the majority of them exhibited a selectivity index (SI) ranging from 2.78 to 15.58, which suggests that these compounds may be a promising class of substances with antimalarial activity.
