Alzheimer’s disease (AD) is a multifactorial incurable neurodegenerative disorder. To date, cholinesterase inhibitors (ChEI) are the mainstay line of treatment to ameliorate the symptoms of AD. Tacrine and donepezil are considered two important cornerstones of anti-dementia drugs. Accordingly, novel series of hexahydrobenzothienocyclopentapyridines, octahydrobenzo-thienoquinolines, hexahydrocyclopenta(thienoquinoline/thienodipyridine), and octahydropyrido-thienoquinolines were efficiently synthesized from readily available reagent, e.g. cyclohexanones, cyclopentanone, and 1-methyl-piperidin-4-one to afford 14 new compounds. All new compounds were screened against their acetylcholinesterase, butyrylcholinesterase, and β-amyloid protein inhibition. In AChE inhibition assay, compound 3,7-dimethyl-1,2,3,4,7,8,9,10-octahydrobenzo[4,5]thieno[2,3-b]quinolin-11-amine (2h) showed IC50 value 9.24 ± 0.01 μM × 10−2 excelling tacrine. Compound 1,7-dimethyl-1,2,3,4,7,8,9,10-octahydrobenzo[4,5]thieno[2,3-b]quinolin-11-amine (2e) possess excellent IC50 values 0.58 ± 0.02 μM × 10−2 and 0.51 ± 0.001 μM × 10−4 for both butyrylcholinesterase and β-amyloid protein inhibition assays, sequentially. In silico ADME studies were investigated for the promising members (octahydrobenzo-thienoquinolines 2c, 2d, 2e, 2h, 2i, and octahydropyrido-thienoquinolines 4e) and all the results were illustrated. A comparative docking study was conducted between the promising members and both tacrine and donepezil in both acetyl and butyryl choline active sites. The results revealed extra binding patterns and good agreement with the biological results.
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