Title:Design, Synthesis and Molecular Docking Studies of New Potential Piperazine Derivatives as Cognition Enhancers
Volume: 17
Issue: 2
Author(s): Chhanda C. Danta and Poonam Piplani*
Affiliation:
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014,India
Keywords:
Acetylcholinesterase inhibitor, alzheimer, cognitive dysfunction, molecular docking, passive avoidance, piperazine
hybrid.
Abstract: Background: In 2016, the statistical reports stated that Alzheimer is not just memory loss
but it kills and has become the 6th leading cause of death. The number of dementia patients is increasing
rapidly and expected to rise to 131.5 million by 2050. Still there is not a drug candidate that can cure
the cognitive deficits completely.
Objective: Series of novel piperazine derivatives have been designed, synthesized and evaluated for
cognition enhancing activity.
Methods: The synthesized compounds were screened for their
in vitro AChE inhibition and reversal of
scopolamine induced memory deficit in a passive avoidance stepdown animal model in mice. Enzyme
kinetics and molecular docking studies were carried out to elucidate the mechanism of AChE inhibition.
Results: All the compounds exhibited excellent IC
50 values with potential dual binding site inhibition
activity. The IC
50 values and inhibition constants of the most promising compounds
1d and
3c were
found to be 2.23 μM, 1.05 μM, 14.38 μM and 6.93 μM respectively. They potentially reversed the scopolamine
induced memory deficit at a dose of 1.0 mg/kg i.p. in mice. Furthermore,
1d and
3c showed
high CNS penetration and brain AChE inhibition in
ex vivo experiments. Additionally, significant free
radical scavenging activity was determined taking trolox as the standard.
Conclusion: Compounds
1d and
3c were emerged as promising of the series and further can be investigated
for the future pursuit as drug candidates.
