AUTHOR=Xu Jing-Jing , Luo Jiao , Xi Heng , Xu Jin-Bu , Wan Lin-Xi 

TITLE=Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues

JOURNAL=Frontiers in Chemistry

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1282978

DOI=10.3389/fchem.2023.1282978

ISSN=2296-2646

ABSTRACT=<p>A series of novel <italic>N</italic>-aryl-debenzeyldonepezil derivatives (<bold>1–26</bold>) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer’s disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. <italic>In vitro</italic> cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue <bold>13</bold> possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H<sub>2</sub>O<sub>2</sub>-induced injury in SH-SY5Y cells. Furthermore, Compound <bold>13</bold> did not show significant cytotoxicity on SH-SY5Y. These results suggest that <bold>13</bold> is a potential multifunctional active molecule for treating Alzheimer’s disease.</p>