Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity |
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| Authors: | Matthias D’hooghe Karel Vervisch Karl W Törnroos Tom Verhaeghe Tom Desmet Carmen Lategan Peter J Smith Kelly Chibale Norbert De Kimpe |
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| Institution: | 1. Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium;2. Department of Chemistry, University of Bergen, Allégt 41, 5007 Bergen, Norway;3. Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium;4. Medical School, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory 7925, South Africa;5. Department of Chemistry and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa |
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| Abstract: | 2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH4-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures. Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II. |
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