Indole-based heterocyclic conjugates: Design, synthesis, in silico studies and cholinesterase inhibition

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Alzheimer's disease (AD), characterized by cognitive decline, behavioral changes, and amnesia, ultimately leads to dementia in older people. Despite decades of study, there is still no effective way to prevent, retard, or reduce the symptoms of AD. In this paper, we report indole-based heterocyclic conjugates as cholinesterase inhibitors. Compounds 14c (IC50s AChE = 0.30 µM; BuChE = 10.16 µM) and 14h (IC50s AChE = 0.58 µM; BuChE = 15.13 µM) display efficacy against both AChE and BuChE. These derivatives did not exhibit toxicity against the HEK-293 and SH-SY5Y cell lines. Docking analysis demonstrated better binding affinity of these compounds (docking score, 14c = –9.06 kcal/mol; 14h = –9.03 kcal/mol) with recombinant human acetylcholinesterase (PDB ID:- 4EY7) as compared to the reference drug donepezil (–8.52 kcal/mol). Molecular dynamics analysis demonstrated better MMGBSA binding free energy of these compounds (14c = –33.10 kcal/mol; 14h = –36.64 kcal/mol) with recombinant human acetylcholinesterase as compared to the reference drug donepezil (-32.20 kcal/mol). These compounds bind in the active site of acetylcholinesterase and maintain stability similar to donepezil during a 200 ns MD simulation. Moreover, these compounds exhibit recognizable ADME characteristics.