Design, synthesis and biological evaluation of Indanone derivatives bearing Carbamates functional groups as novel acetylcholinesterase inhibitors with the outlook of anti-Alzheimer drug development

Abstract

Introduction: Alzheimer's disease is the most common form of dementia. Aims: AD is expected to be one of the leading causes of death globally in the coming years. As a result, the design, synthesis, and biological evaluation of compounds can effectively inhibit cholinesterase. Methods: In this study, inspired by indanone and carbamate moieties of donepezil and rivastigmine, a series of derivatives were designed and synthesized according to pharmacophore hybridization-based strategy. The cholinesterase inhibitory activity of the synthesized compounds was evaluated by Ellman method. Also, the inhibition of Aβ aggregation and neuroprotective effect were investigated. The binding mode of the compound was studied by molecular docking calculations. Finally, stability and the reversibility of enzyme-inhibitor interaction were investigated for the selected compound. Results: The synthesized compounds were identified by IR, 1H NMR, 13C NMR, elemental analysis, and all were confirmed. Also, the results of biological tests showed that some derivatives were active for AChE and BChE. Among them, compounds 7h exhibited the highest inhibitory effect on AChE and BChE, 1.2 and 0.3 µM. 7h derivative inhibited (86.8%) self-induced Aβ aggregation stronger than that of donepezil (45.5%). Also, it showed good neuroprotective activity against H2O2 induced oxidative stress at 10 and 100 μM concentrations. A kinetic confirmed a reversible partial non-competitive type of AChE inhibition. According to this, an allosteric binding site was proposed, and the mode of binding was predicted using a molecular docking study. Since the synthesized compounds were carbamate derivatives, the stability was evaluated under cholinesterase inhibition assay condition by HPLC method. Inhibitor was stable under assay conditions even after a long incubation time for 24 hours. The reversibility of enzyme-inhibitor interaction was investigated and rules out pseudo-irreversible inhibition. Conclusion: The current investigation results may provide valuable information for further anti-Alzheimer drug discovery programs based on the indanone-carbamate scaffold.