Synthesis and 2D-QSAR study of dispiropyrrolodinyl-oxindole based alkaloids as cholinesterase inhibitors

Bioorg Chem. 2019 Mar:83:226-234. doi: 10.1016/j.bioorg.2018.10.030. Epub 2018 Oct 22.

Abstract

In this work, we describe the regioselective synthesis of some new dispiro[indene-2,3'-pyrrolidine-2',3″-indoline]-1,2″(3H)-dione 4-29 attributable to the previously described methods. All the new chemical entities were assessed in-vitro as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes; while no significant inhibitory activity for the tested compounds were assigned on AChE, compounds 4, 27, 29, 28 and 15 were the most active against BChE enzyme with IC50 = 13.7 µM, 21.8 µM, 22.1 µM, 22.9 µM and 24.9 µM respectively compared to Donepezil (IC50 = 0.72 µM). Compound 4 was found to have a mixed type mode of inhibition, the bioactivity of the new chemical entities (N = 26, n = 5, R2 = 0.893, R2 cvOO = 0.831, R2 cvMO = 0.838, F = 33.32, s2 = 0.003) was elucidated via a statistically significant QSAR model utilizing CODESSA-Pro software that validated the observed results.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Donepezil; Oxindole.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Butyrylcholinesterase / chemistry
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Molecular Structure
  • Oxindoles / chemical synthesis
  • Oxindoles / chemistry*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Quantitative Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Oxindoles
  • Pyrrolidines
  • Acetylcholinesterase
  • Butyrylcholinesterase