Synthesis, biological evaluation and molecular modeling studies of novel carbazole-benzylpiperazine hybrids as acetylcholinesterase and butyrylcholinesterase inhibitors

A novel series of carbazole-benzylpiperazine hybrids (7a-n) were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated. The biological results indicated that the nature of linker between carbazole and benzylpiperazine moieties as well as the type of substitutions on the phenyl ring of benzylpiperazine moiety greatly affected the inhibitory activity and selectivity of the synthesized compounds towards eelAChE and eqBuChE enzymes. Among all the synthesized compounds, compounds 7a (IC50 = 8.9 mu M) and 7e (IC50 = 5.7 mu M) with fluorine substitution at meta and para positions of the phenyl ring showed the highest inhibitory activity against eelAChE and maximum inhibitory activity against eqBuChE were generated by compounds 7h (IC50 = 5.4 mu M) and 7k (IC50 = 4.5 mu M) with fluorine and methyl substitutions at meta position of the phenyl ring, respectively. Furthermore, kinetic analysis and molecular modeling studies revealed that the most active compound 7e acts as a mixed-type inhibitor against AChE, which suggested this compound interacted with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE enzyme.