Design and synthesis of newer potential 4-(N-acetylamino)phenol derived piperazine derivatives as potential cognition enhancers

• The synthesized piperazine derivatives were found to be potent dual binding site inhibitors of acetylcholinesterase enzyme.
• Compounds 1b and 2d displayed excellent IC50 values of 1.66 μM and 0.49 μM respectively.
• Showed significant antiamnesic activity at a dose of 1.0 mg/kg.
• Have CNS penetration and brain AChE inhibition abilities.
• May be used as leading compounds in the future drug design.

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 1.66 μM and 0.49 μM and competitive inhibitor constant Ki 43.66 μM and 4.10 μM 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 1.0 mg/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.

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