Hamulakova_2012_Eur.J.Med.Chem_55_23

New tacrine derivatives 5a-d 6a-d with piperazino-ethyl spacer linked with corresponding secondary amines and tacrine homodimer 8 were synthesized and tested as cholinesterase inhibitors on human acetylcholinesterase hAChE and human plasmatic butyrylcholinesterase hBChE In most cases the majority of synthesized derivatives exhibit a high AChE and BChE inhibitory activity with IC(50 values in the low-nanomolar range being clearly more potent than the reference standard tacrine 9-amino-1,2,3,4-tetrahydroacridine 1 and 7-MEOTA 7-methoxy-9-amino-1,2,3,4-tetrahydroacridine Among them inhibitors 8 and 5c showed a strong inhibitory activity against hAChE with an IC(50 value of 4.49 nM and 4.97 nM resp and a high selectivity to hAChE The compound 5d acted as the most potent inhibitor against hBChE with an IC(50 value of 33.7 nM and exhibited also a good selectivity towards hBChE The dissociation constants K(i of the selected inhibitors were compared with their IC(50 values Molecular modeling studies were performed to predict the binding modes between individual derivatives and hAChE/hBChE.