The Design, Synthesis And Activity Of Novel Acetylcholinesterase Inhibitors

AChE is a protein closely correlative with synaptosome. The hydrolysis of neurotransmitter-acetylcholine in the cholinergic synaptic cleft was regulated by AChE. Acetylcholinesterase inhibitors(AChEIs) which decrease the hydrolysis of acetylcholine but increase acetylcholine amount in synaptic cleft. Acetylcholinesterase inhibitors can use as the pesticides and the medicine for the treatment of Alzheimer's.It was reported that some nitroguanidine derivatives(including its bioisosteres-cyano guanidine, nitro acetamidine) and 2-(nitroimino)-imida-zoline were developped as acetylcholinesterase inhibitors. By comparison of the binding model of the known AChEIs with acetylcholinesterase and the new nicotine insecticides which contain 2-(nitroimino) imidazoline with the N-type acetylcholine receptor(nAChR), nitroguanidine and its bioisosteres were proposed to be used as important pharmacophore in novel acetylcholinesterase inhibition design at the first time.In this study, a tricyclic cyano guanidine compound with strong acetylcholinesterase inhibitory activity was used as the lead compound, seven ring-opening derivatives were prepared. With the aim to retain cationic properties and at the same time increase the binding sites in AChE, 5-amino of Huperzine A simplified structure and 9-amino of tacrine were substituted with 2-(nitroimino)-acetamidine and cyano-guanidine, respectively.17 compounds were synthesized. Based on AChE spacestructure, we selected two ligands to bind the active center and peripheral anionic site of AChE, respectively, two triazole-phthalimide hybrids were prepared. The structures of these compounds were characterized by MS,1H and 13CNMR spectroscopy. The in vitro acetylcholinesterase activity tests were carried out to evaluate the activity of these compounds. Five compounds showed moderate inhibitory activity to AChE, a compound showed micro-molar activity. These results built up a solid foundation for further research.