Chemosensitization of a Multidrug-Resistant Leishmania tropica Line by New Sesquiterpenes from Maytenus magellanica and Maytenus chubutensis

Parasite resistance to drugs has emerged as a major problem in current medicine, and therefore, there is great clinical interest in developing compounds that overcome these resistances. In an intensive study of South American medicinal plants, herein we report the isolation, structure elucidation, and biological activity of dihydro-β-agarofuran sesquiterpenes from the roots of Maytenus magellanica (1−14) and M. chubutensis (14−17). This type of natural products may be considered as privileged structures. The structures of 10 new compounds, 1, 3, 6−9, and 12−15, were determined by means of ¹H and ¹³C NMR spectroscopic studies, including homonuclear (COSY and ROESY) and heteronuclear correlation experiments (HMQC and HMBC). The absolute configurations of eight hetero- and homochromophoric compounds, 1, 3, 6−9, 12, and 13, were determined by means of CD studies. Fourteen compounds, 1−3 and 6−16, have been tested on a multidrug-resistant Leishmania tropica line overexpressing a P-glycoprotein-like transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. From this series, 1, 2, 3, 14, and 15 showed potent activity, 1 being the most active compound. The structure−activity relationships of the different compounds are discussed.