title: Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer's disease.
abstract: 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.
authors: Institute of Chemistry, Faculty of Science, P. J. Safarik University, Moyzesova 11, SK-04167 Kosice, Slovak Republic. slavka.hamulakova@upjs.sk
authors: Slavka
authors: S
authors: Hamulakova
authors: Ladislav
authors: L
authors: Janovec
authors: Martina
authors: M
authors: Hrabinova
authors: Pavol
authors: P
authors: Kristian
authors: Kamil
authors: K
authors: Kuca
authors: Maria
authors: M
authors: Banasova
authors: Jan
authors: J
authors: Imrich
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D011487:Protein Conformation; D013619:Tacrine / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002800:Cholinesterase Inhibitors; D010879:Piperazines; D000077489:Piperazine; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase