Imino-2H-Chromene Based Derivatives as Potential Anti-Alzheimer's Agents: Design, Synthesis, Biological Evaluation and in Silico Study

Abstract

A new series of imino-2H-chromene derivatives were rationally designed and synthesized as novel multifunctional agents against Alzheimer's disease. A set of phenylimino-2H-chromenes as well as the newly synthesized iminochromene derivatives were evaluated as BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitors. The results indicated that among the iminochromene set, 10c bearing fluorobenzyl moiety was the most potent BACE1 inhibitor with an IC₅₀ value 6.31 μM. In vitro anti-cholinergic activities demonstrated that compound 10a bearing benzyl pendant was the best inhibitor of AChE (% inhibition at 30 μM=24.4) and BuChE (IC₅₀ =3.3 μM). Kinetic analysis of compound 10a against BuChE was also performed and showed a mixed-type inhibition pattern. The neuroprotective assessment revealed that compound 11b, a phenylimino-2H-chromene derivative with hydroxyethyl moiety, provided 32.3 % protection at 25 μM against Aβ-induced PC12 neuronal cell damage. In addition, docking and simulation studies of the most potent compounds against BACE1 and BuChE confirmed the experimental results.

Keywords: Alzheimer's disease; BACE1 inhibitor; ChE inhibitor; imino-2H-chromene; neuroprotection.