Aminosteroids from Buxaceae and Apocynaceae Plants as Antiprotozoal Agents: Structural Diversity and Structure–Activity Relationships

As part of our search for new natural chemicals with bioactivity against protozoan pathogens, we have previously reported on the isolation, identification and antiprotozoal activity of over 100 alkaloids with an aminosteroid or related scaffold. We have now investigated the hypothesis that these chemically related compounds also share common mechanisms of action regarding their activity against Trypanosoma brucei rhodesiense (human East African trypanosomiasis) and Plasmodium falciparum (tropical malaria). Furthermore, their cytotoxic activity against mammalian cells (L6 rat skeletal myoblasts) was also included in the investigation. We found that mammalian cytotoxicity is generally lower and there is only a low degree of mutual correlation between the susceptibility of the two parasites and mammalian cells to the compounds’ toxic effects. With the molecular targets being unknown, the 3D-QSAR study was conducted using the Open3Dqsar software. The resulting models show the main structural features influencing the different biological effects. They indicate that indeed related molecular targets underly the cytotoxic, antitrypanosomal and antiplasmodial activity based on structural determinants sufficiently different enough to warrant a significant level of parasite-selectivity. The results of this study offer structural explanations for the observed differences in aminosteroids’ action against the mentioned pathogens and provide a starting point for optimization and simplification of the natural structures towards leads for antiprotozoal drug development.