title: 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.
authors.affiliation: Department of Chemistry, Yogi Vemana University, Kadapa, India.
authors.forename: Jeelan Basha
authors.initials: JB
authors.lastname: Shaik
authors.affiliation: Centre for Bioinformatics, School of life Sciences, Pondicherry Central University, Puducherry, India.
authors.forename: Bhagath Kumar
authors.initials: BK
authors.lastname: Palaka
authors.affiliation: Department of Chemistry, Yogi Vemana University, Kadapa, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Penumala
authors.affiliation: Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Eadlapalli
authors.affiliation: Department of Chemistry, University College of Sciences, Sri Venkateswara University, Tirupati, India.
authors.forename: Manidhar
authors.initials: M
authors.lastname: Darla Mark
authors.affiliation: Centre for Bioinformatics, School of life Sciences, Pondicherry Central University, Puducherry, India.
authors.forename: Dinakara Rao
authors.initials: DR
authors.lastname: Ampasala
authors.affiliation: Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Vadde
authors.affiliation: Department of Chemistry, Yogi Vemana University, Kadapa, India.
authors.forename: Damu
authors.initials: D
authors.lastname: Amooru Gangaiah
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D062105:Molecular Docking Simulation
chemical_list: D016229:Amyloid beta-Peptides; D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Aβ1−42 aggregation; Kinetic study; acetylcholinesterase; antioxidant; butyrylcholinesterase; coumarin; docking