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.

Design and synthesis of multipotent 3-aminomethylindoles and 7-azaindoles with enhanced protein phosphatase 2A-activating profile and neuroprotection

“…The multi-target based drug design has unsuccessfully pursued an efficient cure for AD in the last two decades [62,63]. The classical multi-target strategies keep paying attention to design principally cholinergic drugs possessing an additional pharmacological activity [64][65][66][67][68][69]. Besides, there is an increasing interest in exploring other therapeutic alternatives, sustained by the discovery of new biological targets implicated in AD that possess a potential druggability, such as the search of microtubule-stabilizing agents [70] or drugs suppressing NMDA receptors active subunits [71].…”

Design, synthesis, biological evaluation, and molecular dynamics of novel cholinesterase inhibitors as anti‐Alzheimer's agents

“…Flavonoids and homoisoflavonoids (3‐benzylidene chroman‐4‐one) are important compounds with a broad spectrum of biological activities, such as the anti‐AChE activity, monoamine oxidase‐B inhibitory effect, corticosteroid inhibitory activity, anticancer, and antimicrobial properties, neuroprotection capability, amyloid‐β fibril formation inhibitory activity, and 15‐lipoxygenase inhibitory effect . In continuation of our research program on the efficient synthesis of newly prepared organic compounds, and potentially interesting biological active compounds, herein, we designed and synthesized novel series of chroman‐4‐one derivatives bearing aminoalkoxy moiety at the 7‐position of the 3‐benzylidene chroman‐4‐ones and evaluated their anti‐AChE and anti‐BuChE activities (Figure ).…”

Facile Synthesis and Anticancer Activity Study of Novel Series of Substituted and Fused Coumarin Derivatives

“…Anticancer [1][2][3], antibacterial [4], antiviral [5], anti-inflammatory [6], anticoagulant [7], acetyl, and butyryl cholinesterase inhibitory activity [8,9] are widely reported biological activities of various coumarin derivatives. Anticancer [1][2][3], antibacterial [4], antiviral [5], anti-inflammatory [6], anticoagulant [7], acetyl, and butyryl cholinesterase inhibitory activity [8,9] are widely reported biological activities of various coumarin derivatives.…”