New series of aromatic amides hybrids derivatives as anti-Alzheimer's drugs: Design, synthesis, biological activity and computational studies

Alzheimer's disease (AD) is a degenerative disease of the central nervous system with complex pathogenesis there is an urgent need to develop more relevant agents. Since Gx-50 has some anti-AD activity and its cinnamic acid fragment can be regarded as an advantaged fragment, it was suggested to splice it and similar fragment to compound 3 which showed anti-AD activities in previous work. Then 20 compounds were obtained and among them, compound 1b has better acetylcholinesterase inhibitory activity (IC₅₀ = 0.29 μM), which was equivalent to the positive drug donepezil, and its molecular docking showed cinnamic acid part of compound 1b provide more bind possibilities with hAChE. Also, compound 1b showed neuroprotection effect (cell survival rate is 76.72 % at 12.5 μM), and revealed by ROS analysis and immunofluorescence, its neuroprotection activity may act by reducing ROS-induced oxidative stress. Besides, 10b also exhibits activity in inhibiting acetylcholinesterase (IC₅₀ = 0.31 μM) and Aβ aggregation (IC₅₀ = 25.0 μM), making it potential for further development. In summary, it studied the feasibility of molecular hybridization, adn provided new promising multi-functional agent for anti-AD.