Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents

Eur J Med Chem. 2016 Jan 1:107:219-32. doi: 10.1016/j.ejmech.2015.10.046. Epub 2015 Oct 31.

Abstract

A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 μM which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98-15.99 μM). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 ± 0.0007 μM) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 ± 0.77 μM). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (Ki1 0.0103 μM and Ki2 0.0193 μM). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of Aβ induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti-Alzheimer agents.

Keywords: ADMET; Acetylcholinesterase; Alzheimer's disease; Antioxidant; Butyrylcholinesterase; Fused tricyclic coumarin; Molecular modeling study; Neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Animals
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Binding Sites
  • Butyrylcholinesterase / metabolism
  • Chemistry Techniques, Synthetic
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Computer Simulation
  • Coumarins / chemical synthesis
  • Coumarins / chemistry*
  • Coumarins / pharmacology*
  • Drug Evaluation, Preclinical / methods
  • Galantamine / pharmacology
  • Humans
  • Hydrogen Peroxide / toxicity
  • Male
  • Mice, Inbred BALB C
  • Models, Molecular
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry*
  • Neuroprotective Agents / pharmacology*
  • Neurotoxicity Syndromes / etiology

Substances

  • Antioxidants
  • Cholinesterase Inhibitors
  • Coumarins
  • Neuroprotective Agents
  • Galantamine
  • Hydrogen Peroxide
  • Acetylcholinesterase
  • Butyrylcholinesterase