Recent studies have shown that aphidicolin, a secondary metabolite of the endophytic fungus Nigrospora sphaerica, has high activity against the protozoan Leishmania major. Despite its promising leishmanicidal potential, aphidicolin presents a therapeutically unsuitable physico-chemical and pharmacokinetic profile. In this sense, a review of the literature shows the limited types of modification for this terpene. In addition, it gives an idea about the molecular properties of the compounds produced and which were correlated to leishmanicidal derivatives. This analysis provided us a rationale for the development of an oxime derivative. We synthesized the oxime-aphidicolin and a series of derivatives for a preliminary evaluation of the structural requirements for the leishmanicidal activity of aphidicolin and its semisynthetic derivatives. Eight compounds have been synthesized and tested against different species of the Leishmania protozoa. The preliminary evaluation demonstrated high leishmanicidal activity for aphidicolin, while the oxime derivative shows moderate selectivity for the L. braziliensis species, which is commonly found in several South American countries. None of the compounds showed cytotoxicity against mammalian cells.
diterpenes; aphidicolin; Leishmania spp.; semisynthesis; molecular properties
