Cholinesterase Inhibitory Activity and Molecular Docking Studies of Isocryptolepine‐Triazole Adducts

Abstract Due to the rising prevalence of Alzheimer's disease (AD), there is a pressing need for more effective drugs to treat or manage AD's symptoms. Studies have shown that cholinesterase inhibition can improve cognitive and behavioral symptoms associated with AD, by addressing the cholinergic deficit. Based on the recent development of cholinesterase inhibitors with indoloquinoline and triazole moiety, we rationalized that compounds with an isocryptolepine‐triazole scaffold may also have the same biological targets. In this study, eighteen previously synthesized isocryptolepine‐triazole compounds were assessed for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The majority of these compounds demonstrated potent selective AChE inhibition. Furthermore, our molecular docking and molecular dynamic simulation studies reveal that the isocryptolepine and triazole moieties are important for the binding of the compounds with the periphery of the AChE's binding pocket. While reductions in molecular weights and lipophilicities may be necessary to improve their pharmacokinetic properties, this work provides valuable insights for designing future AChE inhibitors, based on the novel isocryptolepine‐triazole scaffold.