Antileishmanial activities of aphidicolin and its semisynthetic derivatives

Aphidicolin and a series of semisynthetic aphidicolan derivatives have been identified in in vitro tests as novel drugs with antiparasitic potential. All compounds have been tested against extracellular promastigotes of Leish mania donovani, L. infantum, L. enriettii, and L. major and against intrace llular amastigotes of L. donovani in murine macrophages. The compounds show ed antileishmanial activity at concentrations in the microgram range (50% e ffective concentration [EC50] = 0.02 to 1.83 mug/ml). The most active deriv ative (aphidicolin-17-glycinate hydrochloride) had EC(50)s of 0.2 mug/ml ag ainst extracellular and 0.02 mug/ml against intracellular L. donovani paras ites. To validate the pharmacological potential of tested drugs, pharmacolo gical safety was determined by testing all compounds against two neoplastic cell lines (squamous carcinoma [KB] and melanoma [SK-Mel]) and against mur ine bone marrow-derived macrophages as host cells. With minor exceptions on ly for macrophages, tested aphidicolans did not shelf significant cytotoxic ity (EC50 > 25.0 mug/l). Structure-activity relationships of these aphidico lan derivatives are discussed.