New diaryl-substituted azabicyclo[3.2.2]nonanes and their antiprotozoal potencies

摘要

Several new diaryl-substituted azabicyclo[3.2.2]nonanes with varying substitution patterns of the aromatic rings and differing amino substitution at a bridgehead atom of the bicyclic ring system were synthesized from bicyclo[2.2.2]octan-2-ones via Schmidt or Beckmann reactions and subsequent reduction. The bicyclic octanones were prepared in a one-pot synthesis from acyclic starting materials or in one step from properly functionalized diarylcyclohexanones which were accessible by a catalyzed Diels-Alder reaction. The characterization of the new compounds was done by UV/Vis spectroscopy, FT-IR spectroscopy, and HRMS. Structural elucidation of isomers was done by NMR spectroscopy using 1D and 2D techniques as well as NOE measurements. The antiprotozoal activities against Plasmodium falciparum K (1) , resistant to chloroquine and pyrimethamine, and against Trypanosoma brucei rhodesiense as well as the cytotoxicities of the new compounds were determined and compared to those of reported compounds. Structure-activity relationships are discussed.