Novel cinnamic acid-tryptamine hybrids as potent butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study

A novel series of cinnamic acid-tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid-tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 +/- 0.04M. This compound showed a 14-fold higher inhibitory potency than the standard drug donepezil (IC50=7.79 +/- 0.81M) and inhibited BChE through a mixed-type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against -secretase, which exhibited low activity (inhibition percentage: 38%).