Antioxidant and acetylcholinesterase inhibition activity of aliphatic and aromatic edaravone derivatives

As Alzheimer disease (AD) is a multifactorial condition, it should be tackled with drugs targeting multiple key pathways. A series of aliphatic (2–8) and aromatic (9–15) edaravone derivatives were synthesized, characterized, and evaluated as antioxidant agents using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2-2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS·⁺) assays, as well as acetylcholinesterase (AChE) inhibitors. In both antioxidant assays, even though the starting compound edaravone was more active, the best derivative was 5 with 50% effective concentration (EC₅₀) of 0.0301 and 0.8106 mM respectively, followed by 3 (EC₅₀ of 0.1920 mM and 3.5311 mM). In the AChE inhibition assay, the derivatives were not as active as the positive control galantamine, but a general better activity was shown from the aromatic compounds. The best results were for 10, with 41.9% of inhibition (concentration of 150 μg/mL), and 9 with 31.6%. Docking analysis of compound 10 showed hydrogen bonds with residues Ser200 and His440 in the AChE catalytic gorge. All synthesized derivatives 2–15 presented drug-like properties and are capable of crossing the blood–brain barrier and not be pumped out of it. These results indicate edaravone derivatives can function as scaffolds for AD drugs, though further derivatizations should be conducted to improve their antioxidant and AChE inhibition profiles. [Figure not available: see fulltext.]