Author/Authors :
Nadri, Hamid yazd shahid sadoghi university of medical sciences - Faculty of Pharmacy and Neurobiomedical Research Center - Department of Medicinal Chemistry, ايران , Pirali-Hamedani, Morteza tehran university of medical sciences tums - Faculty of Pharmacy and Pharmaceutical Sciences Research Center, تهران, ايران , Moradi, Alireza yazd shahid sadoghi university of medical sciences - Faculty of Pharmacy and Neurobiomedical Research Center - Department of Medicinal Chemistry, ايران , Sakhteman, Amirhossein yazd shahid sadoghi university of medical sciences - Faculty of Pharmacy and Neurobiomedical Research Center - Department of Medicinal Chemistry, ايران , Vahidi, Alireza yazd shahid sadoghi university of medical sciences - Herbal Medicine Center, ايران , Sheibani, Vahid kerman university of medical sciences - Neuroscience Research Center, ايران , Asadipour, Ali kerman university of medical sciences - Neuroscience Research Center, ايران , Hosseinzadeh, Nouraddin tehran university of medical sciences tums - Drug design Development Research Center, تهران, ايران , Abdollahi, Mohammad tehran university of medical sciences tums - Faculty of Pharmacy and Pharmaceutical Sciences Research Center, تهران, ايران , Shafiee, Abbas tehran university of medical sciences tums - Faculty of Pharmacy and Pharmaceutical Sciences Research Center, تهران, ايران , Foroumadi, Alireza kerman university of medical sciences - Neuroscience Research Center, ايران , Foroumadi, Alireza tehran university of medical sciences tums - Drug design Development Research Center, تهران, ايران
Abstract :
Background: Several studies have been focused on design and synthesis of multi-target anti Alzheimer compounds. Utilizing of the dual Acetylcholinesterase/Butyrylcholinesterase inhibitors has gained more interest to treat the Alzheimer’s disease. As a part of a research program to find a novel drug for treating Alzheimer disease, we have previously reported 6-alkoxybenzofuranone derivatives as potent acetylcholinesterase inhibitors. In continuation of our work, we would like to report the synthesis of 5,6-dimethoxy benzofuranone derivatives bearing a benzyl pyridinium moiety as dual Acetylcholinesterase/ Butyrylcholinesterase inhibitors. Methods: The synthesis of target compounds was carried out using a conventional method. Bayer-Villiger oxidation of 3,4-dimethoxybenzaldehyde furnished 3,4-dimethoxyphenol. The reaction of 3,4-dimethoxyphenol with chloroacetonitrile followed by treatment with HCl solution and then ring closure yielded the 5,6-dimethoxy benzofuranone. Condensation of the later compound with pyridine-4-carboxaldehyde and subsequent reaction with different benzyl halides afforded target compounds. The biological activity was measured using standard Ellman’s method. Docking studies were performed to get better insight into interaction of compounds with receptor. Results: The in vitro anti acetylcholinesterase/butyrylcholinesterase activity of compounds revealed that, all of the target compounds have good inhibitory activity against both Acetylcholinesterase/Butyrylcholinesterase enzymes in which compound 5b (IC50 = 52 ± 6.38nM) was the most active compound against acetylcholinesterase. The same binding mode and interactions were observed for the reference drug donepezil and compound 5b in docking study. Conclusions: In this study, we presented a new series of benzofuranone-based derivatives having pyridinium moiety as potent dual acting Acetylcholinesterase/ Butyrylcholinesterase inhibitors.
