Design, Synthesis, and Testing of Antiprotozoal Activity of Primin and Analogues

Conformationally restricted analogues of the natural product primin were synthesized as potential antiprotozoal agents. The synthesis utilizes quinone C-H functionalization methods to enable an efficient and easy access to primin analogues. The antiprotozoal activities of this series were evaluated in a panel of parasites and compared to the natural product primin. For all the synthesized primin analogues a potent in vitro activity was found against the pathogen Trypanosoma brucei rhodesiense (IC50 0.05 μg/mL). The observed antiprotozoal activity is not related to the production of reactive oxygen species (ROS). Initial results of the in vivo experiments with a T. b. rhodesiense rodent animal model of the human disease were also reported. Intraperitoneal injection administration of compound 7 resulted in complete clearance of T. b. rhodesiense in the tested rodent animals 24 hours after the last treatment. Our results show that the primin scaffold represents a new scaffold for further development of potent inhibitors of Trypanosoma brucei rhodesiense.