Design, synthesis and evaluation of novel multi-target-directed ligands for treatment of Alzheimer's disease based on coumarin and lipoic acid scaffolds

Jalili-Baleh L., Forootanfar H., Kucukkilinc T. T., Nadri H., Abdolahi Z., Ameri A., ...More

European Journal of Medicinal Chemistry, vol.152, pp.600-614, 2018 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 152
  • Publication Date: 2018
  • Doi Number: 10.1016/j.ejmech.2018.04.058
  • Journal Name: European Journal of Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.600-614
  • Keywords: Alzheimer's disease, Coumarin, Lipoic acid, Neuroprotective agents, Antioxidant, MTDLs, SITE ACETYLCHOLINESTERASE INHIBITORS, OXIDATIVE STRESS HYPOTHESIS, AMYLOID-BETA, ANTICHOLINESTERASE ACTIVITY, BIOLOGICAL EVALUATION, ANTIOXIDANT ACTIVITY, DIHYDROLIPOIC ACID, HYDROGEN-PEROXIDE, CELL-DEATH, DERIVATIVES
  • Hacettepe University Affiliated: Yes

Abstract

A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimer's disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds (5 and 11) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on A beta-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio-metal chelation and neuroprotection against H2O2- and A beta(1.42)-induced cytotoxicity. In the light of these results, the applied hybridization approach introduced new promising lead compound with desired multifunctional properties, being useful in the treatment of Alzheimer's disease. (C) 2018 Elsevier Masson SAS. All rights reserved.