Design, Synthesis, and Study of Novel Memantine Schiff Base Derivatives against Targeted Enzymes in Alzheimer’s Disease

Introduction: According to WHO, Alzheimer’s disease was estimated at 74.4 million cases in 2023, which will increase by 152.8 million cases in 2050. The therapeutic options available in the market for the treatment of AD are only capable of reducing the symptoms of dementia but not preventing progressive degeneration. Memantine is a non-competitive NMDAR antagonist used for the treatment of patients with moderate-to-severe AD, but it has a high toxicity profile. To counter this, the Memantine Schiff base derivatives were designed as simple and lowtoxicity compounds. Materials and Methods: Molecular docking was performed against the targeted enzymes Acetylcholinesterase and Butyrylcholinesterase using AUTODOCK 1.5.7 software. A series of novel Memantine derivatives of Schiff base were synthesized by condensing Memantine with various aryl aldehydes and screened for their invitro-cholinesterase inhibitory activity towards Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) by Ellman’s method. Results and Discussion: Among the designed compounds, compounds LMV and LMC showed maximum binding scores of -10.35 kcal/mol and -10.12 kcal/mol, respectively, than the standard Donepezil (-8.78 kcal/mol) against Acetylcholinesterase. The compounds LMONB and LMDMB produced significant binding scores of -9.31 kcal/mol and -9.11 kcal/mol, respectively, compared to the standard Donepezil (-7.57 kcal/mol) against Butyrylcholinesterase. Also, compounds LMV (30.9 ± 2.13 μM) and LMDMB (13.51 ± 1.12 μM) showed potent inhibitory activity against the AChE and BChE. These compounds possess drug-like characteristics and are also capable of crossing the Blood Brain Barrier (BBB). Conclusion: The studied compounds LMV and LMDMB, being non-toxic, obey Lipinski’s rule of 5 and are potential inhibitors against targeted enzymes, which may be promising clinical candidates for treating Alzheimer’s disease.