Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase

Background Acetylcholine deficiencies in hippocampus and cortex, aggregation of beta-amyloid, and beta-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease. Methods Colorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and beta-secretase inhibitory activities, evaluation of inhibitory potency on beta-amyloid (A beta) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action. Result and discussion A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 mu M) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 mu M) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak beta-secretase inhibitory activities. This compound also inhibited aggregation of beta-amyloid (A beta) in self-induced peptide aggregation test at concentration of 10 mu M. Conclusion It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay.