New indole derivatives as multitarget anti-Alzheimer's agents: synthesis, biological evaluation and molecular dynamics

Background: Alzheimer's disease is a neurological disorder that causes brain cells to shrink and die. Aim: Thirteen novel 'oxathiolanyl', 'pyrazolyl' and 'pyrimidinyl' indole derivatives were designed and synthesized as anti-Alzheimer's disease treatment. Method: In vitro enzyme assay was performed against both AChE and BChE enzymes. In addition, antioxidant assay and cytotoxicity on a normal cell line were determined. Molecular docking and dynamic simulations were conducted to confirm the binding mode in both esterases' active sites. In silico absorption, distribution, metabolism, excretion and toxicity studies were also carried out. Results & conclusion: Compounds 5, 7 and 11 exhibited superior inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with IC50 values of 0.042 and 3.003 mu M, 2.54 and 0.207 mu M and 0.052 and 2.529 mu M, respectively, compared with donepezil.

Automated summary

This study designed and synthesized thirteen novel indole derivatives as potential treatments for Alzheimer's disease. In vitro assays were conducted to assess their enzyme inhibitory activity, antioxidant activity, and cytotoxicity. Molecular docking and simulations confirmed their binding mode with esterases. In silico studies on absorption, distribution, metabolism, excretion, and toxicity were also performed. Results showed that compounds 5, 7, and 11 exhibited superior inhibitory activity against acetylcholinesterase and butyrylcholinesterase compared to donepezil.