New Tetracyclic Systems Integrated Thienopyridine Scaffold As An Anti-Dementia Lead: In Silico Study And Biological Screening

Abstract 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 as anti-dementia drugs with potent inhibitory effects. Accordingly, novel series of hexahydrobenzo-thienocyclopentapyridines, octahydrobenzo-thienoquinolines, hexahydrocyclopenta-(thienoquinoline/thienodipyridine) and octahydropyrido-thienoquinolines were efficiently synthesized from readily available reagents e.g. cyclohexanones, cyclopentanone, and 1-methylpiperidin-4-one to afford fourteen new compounds. All new compounds were screened against their acetylcholinesterase, butyrylcholinesterase and β-amyloid protein inhibition. In acetylcholinesterase 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 IC 50 value 9.24 ± 0.01 µM x10 − 2 excelling tacrine itself. Compound 1,7-Dimethyl-1,2,3,4,7,8,9,10-octahydrobenzo[4, 5]thieno[2,3- b ]quinolin-11-amine ( 2e) possessed excellent IC 50 values 0.58 ± 0.02 µM x10 − 2 and 0.51 ± 0.001 µM x10 − 4 for both the 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.