Design, Synthesis and Molecular Docking Studies of New Potential Piperazine Derivatives as Cognition Enhancers.

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 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.