Design, synthesis, and biological evaluation of novel indanone-based hybrids as multifunctional cholinesterase inhibitors for Alzheimer's disease


Shahrivar-Gargari M., Hamzeh-Mivehroud M., Hemmati S., Shahbazi Mojarrad J., Notash B., Tüylü Küçükkılınç T., ...More

Journal of Molecular Structure, vol.1229, 2021 (Peer-Reviewed Journal) identifier identifier

  • Publication Type: Article / Article
  • Volume: 1229
  • Publication Date: 2021
  • Doi Number: 10.1016/j.molstruc.2020.129787
  • Journal Name: Journal of Molecular Structure
  • Journal Indexes: Science Citation Index Expanded, Scopus, Academic Search Premier, Chemical Abstracts Core, INSPEC
  • Keywords: Acetylcholinesterase inhibitor, Alzheimer's disease, Amyloid-beta self-aggregation crystallography analysis, Indanone-carbamate hybrid, Structure-activity relationship, Molecular docking, Neuroprotection, Partial non-competitive mixed-type inhibition, ACETYLCHOLINESTERASE, HYPOTHESIS, MODULATORS, ACHE

Abstract

© 2020New compounds containing indanone and carbamate moieties were designed based on the hybrid pharmacophore approach. The designed compounds were synthesized and fully characterized by using different methods such as IR, Mass, 1H NMR, 13C NMR, and HPTLC. In vitro inhibitory activities of all synthesized compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The compound 3-[(5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl) methyl] phenyl (4-methoxyphenyl) carbamate (4h) showed the best inhibitory activities with IC50 values of 1.20 and 0.30 μM against AChE and BChE, respectively. In addition, this compound showed a β-amyloid self-aggregation inhibitory effect (86.8%), stronger than that of donepezil (45.5%). Moreover, significant neuroprotective activity on PC12 cells against H2O2 induced cell death was demonstrated for compound 4h at 10 and 100 µM concentrations. Kinetic studies using the 4h confirmed a partial non-competitive mixed type of inhibition mechanism on both enzymes. Considering the suggested inhibition mechanism, molecular docking was used to predict the possible allosteric binding mode of 4h with both AChE and BChE enzymes. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multi-target anti-Alzheimer agents.