Synthesis and Biological Activity of Some Benzochromenoquinolinones: Tacrine Analogs as Potent Anti-Alzheimer's Agents

Article abstract of DOI:10.1002/cbdv.201800488

Alzheimer's disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data emphasize the importance of the disease. As AD is a multifactorial illness, various single target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery. In this work, various benzochromenoquinolinones were synthesized and evaluated for their cholinesterase and BACE1 inhibitory activities as well as neuroprotective and metal-chelating properties. Among the synthesized compounds, 14-amino-13-(3-nitrophenyl)-2,3,4,13-tetrahydro-1H-benzo[6,7]chromeno[2,3-b]quinoline-7,12-dione (6m) depicted the best inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC₅₀s of 0.86 and 6.03 μm, respectively. Also, the compound could inhibit β-secretase 1 (BACE1) with IC₅₀=19.60 μm and showed metal chelating ability toward Cu²⁺, Fe²⁺, and Zn²⁺. In addition, docking study demonstrated desirable interactions of compound 6m with amino acid residues characterizing AChE, BChE, and BACE1.