Antileishmanial Activities of Aphidicolin and Its Semisynthetic Derivatives

Abstract

ABSTRACT 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 Leishmania donovani , L. infantum , L. enriettii , and L. major and against intracellular amastigotes of L. donovani in murine macrophages. The compounds showed antileishmanial activity at concentrations in the microgram range (50% effective concentration [EC 50 ] = 0.02 to 1.83 μg/ml). The most active derivative (aphidicolin-17-glycinate hydrochloride) had EC 50 s of 0.2 μg/ml against extracellular and 0.02 μg/ml against intracellular L. donovani parasites. To validate the pharmacological potential of tested drugs, pharmacological safety was determined by testing all compounds against two neoplastic cell lines (squamous carcinoma [KB] and melanoma [SK-Mel]) and against murine bone marrow-derived macrophages as host cells. With minor exceptions only for macrophages, tested aphidicolans did not show significant cytotoxicity (EC 50 > 25.0 μg/ml). Structure-activity relationships of these aphidicolan derivatives are discussed.