New Tacrine–4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties

• Published in: Journal of medicinal chemistry Vol. 55; no. 3; pp. 1303 - 1317
• Main Authors: Fernández-Bachiller, María Isabel, Pérez, Concepción, Monjas, Leticia, Rademann, Jörg, Rodríguez-Franco, María Isabel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.02.2012; Amer Chemical Soc
• Subjects: Acetylcholinesterase - chemistry; Alzheimer Disease - drug therapy; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Blood-Brain Barrier - metabolism; Butyrylcholinesterase - chemistry; Catalytic Domain; Cattle; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Humans; Life Sciences & Biomedicine; Membranes, Artificial; Permeability; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Tacrine - analogs & derivatives; Tacrine - chemical synthesis; Tacrine - chemistry; Tacrine - pharmacology; CAPACITY; OXIDATIVE STRESS; TACRINE-MELATONIN HYBRIDS; A-BETA; TARGETING ACETYLCHOLINESTERASE; DIRECTED LIGANDS; CHOLINESTERASE INHIBITION; FLUORESCEIN; DERIVATIVES; PEPTIDE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201460y

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer’s disease (AD), a new family of tacrine–4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine–4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.