Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease.

Abstract

Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a-q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1-42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy.