A series of novel hybrids has been designed, synthesized and evaluated for cognition enhancing activities through the inhibition of acetylcholinesterase (AChE) and by passive avoidance mouse model. All the compounds showed excellent AChE inhibition activities and potentially reversed the scopolamine induced memory deficit. Enzyme kinetic and molecular docking studies have confirmed their dual binding affinity and mixed type inhibition. Among them, compounds 1b and 2d displayed excellent IC50 values of 1.66μM and 0.49μM and competitive inhibitor constant Ki 43.66μM and 4.10μM respectively. Ex vivo study confirmed their CNS penetration and brain AChE inhibition abilities. Furthermore, 1b and 2d showed significant antiamnesic activity at a dose of 1.0mg/kg as compared to the reference compounds piracetam and rivastigmine. The results indicate that these two compounds emerged to be developed as cognition enhancers worthy of future pursuit.
Keywords: Acetylcholinesterase inhibitors; Antiradical activity; Cognition; Molecular docking; Passive avoidance stepdown; Piperazine derivatives.
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