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 IC50
values with potential dual binding site inhibition
activity. The IC50
values and inhibition constants of the most promising compounds 1d
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
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
were emerged as promising of the series and further can be investigated
for the future pursuit as drug candidates.