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Alzheimer's disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-β deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[b]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC 50 values below 15 μM, while all compounds exhibited BChE inhibition with IC 50 values below 25 μM. Compounds 9 and 12 exhibited AChE inhibitory activities with IC 50 values of 0.51 μM and 0.55 μM, respectively. Compounds 5 and 9 demonstrated excellent inhibitory activity against BChE with IC 50 values of 2.9 μM and 2.48 μM, respectively. Compounds 9, 13, and 14 were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds 10, 11, and 12 exhibited promising effects on learning and memory. Compounds 5, 10, 11, and 12 exhibited promising SAP values of 70.67 %, 71.5 %, 74.33 % and 73.83 %, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-β and TNF-α. Fundamental features of ADMET have been computed in-silico for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)