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

Abstract

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.