Discovery of Novel Bicyclic and Tricyclic Cyclohepta[b]thiophene Derivatives as Multipotent AChE and BChE Inhibitors, In-Vivo and In-Vitro Assays, ADMET and Molecular Docking Simulation

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 IC₅₀ values below 15 μM, while all compounds exhibited BChE inhibition with IC₅₀ values below 25 μM. Compounds 9 and 12 exhibited AChE inhibitory activities with IC₅₀ values of 0.51 μM and 0.55 μM, respectively. Compounds 5 and 9 demonstrated excellent inhibitory activity against BChE with IC₅₀ 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.