Synthesis, design and biological evaluation of novel highly potent tacrine congeners?for the treatment of Alzheimer's disease

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• 作者：Slavka Hamulakova^a ; ^{slavka.hamulakova@upjs.sk} ; Ladislav Janovec^a ; Martina Hrabinova^b ; Pavol Kristian^a ; Kamil Kuca^b ; ^c ; Maria Banasova^a ; Jan Imrich^a
• 关键词：Alzheimer's disease ; Tacrine ; AChE/BChE inhibitors ; Amyloid ; Molecular modeling
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September, 2012
• 年：2012
• 卷：55
• 期：Complete
• 页码：23-31
• 全文大小：948 K

文摘

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.