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.
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-azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo[2.2.1]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.
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. matthias.dhooghe@UGent.be
Matthias
M
D'hooghe
Karel
K
Vervisch
Karl W
KW
Törnroos
Tom
T
Verhaeghe
Tom
T
Desmet
Carmen
C
Lategan
Peter J
PJ
Smith
Kelly
K
Chibale
Norbert
N
De Kimpe
D017607:Aluminum Compounds / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001388:Aziridines / Q000737:chemistry*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D018020:Lithium Compounds / Q000737:chemistry; D062105:Molecular Docking Simulation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D017607:Aluminum Compounds; D000962:Antimalarials; D001388:Aziridines; D001643:Bridged Bicyclo Compounds; D006536:Heptanes; D008024:Ligands; D018020:Lithium Compounds; C116378:bicyclo(2.2.1)heptene; C042073:lithium aluminum hydride