Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies

J Med Chem. 2015 Aug 13;58(15):6018-32. doi: 10.1021/acs.jmedchem.5b00624. Epub 2015 Jul 27.


We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • Behavior, Animal / drug effects
  • In Vitro Techniques
  • Levetiracetam
  • Mice
  • Mice, Inbred C57BL
  • Nootropic Agents / chemical synthesis
  • Nootropic Agents / chemistry
  • Nootropic Agents / pharmacology*
  • Nootropic Agents / therapeutic use
  • Phenotype
  • Piracetam / analogs & derivatives*
  • Piracetam / chemical synthesis
  • Piracetam / chemistry
  • Piracetam / pharmacology
  • Piracetam / therapeutic use


  • Nootropic Agents
  • Levetiracetam
  • Piracetam