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 symptoms AD. Tacrine and donepezil considered two important cornerstones anti-dementia drugs. Accordingly, novel series hexahydrobenzothienocyclopentapyridines, octahydrobenzo-thienoquinolines, hexahydrocyclopenta(thienoquinoline/thienodipyridine), octahydropyrido-thienoquinolines were efficiently synthesized from readily available reagent, e.g. cyclohexanones, cyclopentanone, 1-methyl-piperidin-4-one afford 14 new compounds. All compounds screened against their acetylcholinesterase, butyrylcholinesterase, 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 IC 50 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- 2e possess excellent values 0.58 0.02 0.51 0.001 −4 for both butyrylcholinesterase assays, sequentially. silico ADME studies investigated promising members (octahydrobenzo-thienoquinolines 2c , 2d 2i 4e all results illustrated. A comparative docking study was conducted between tacrine in acetyl butyryl choline active sites. The revealed extra binding patterns good agreement with biological results.