Hamulakova, Slavka; Janovec, Ladislav; Hrabinova, Martina; Kristian, Pavol; Kuca, Kamil; Banasova, Maria; Imrich, Jan
Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer's disease
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 55:23-31, SEP 2012

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 IC50 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 IC50 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 IC50 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 IC50 values. Molecular modeling studies were performed to predict the binding modes between individual derivatives and hAChE/hBChE. (C) 2012 Elsevier Masson SAS. All rights reserved.

DOI:10.1016/j.ejmech.2012.06.051

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