Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions

Bioorg Chem. 2019 Aug:89:103025. doi: 10.1016/j.bioorg.2019.103025. Epub 2019 May 31.

Abstract

The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.

Keywords: 1,3,4-Oxadiazole; 4-Aminopyridine; Acetylcholinesterase; Butyrylcholinesterase; Molecular hybridization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Avoidance Learning / drug effects
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / administration & dosage
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / pharmacology*
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Development*
  • Electrophorus
  • Horses
  • Humans
  • Male
  • Memory / drug effects
  • Mice
  • Molecular Structure
  • Oxadiazoles / administration & dosage
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacology*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects
  • Scopolamine / administration & dosage
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Oxadiazoles
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • 1,3,4-oxadiazole
  • Scopolamine
  • Acetylcholinesterase
  • Butyrylcholinesterase