Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Abstract Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l ‐tryptophan, 3a‐1–3d‐1 , were designed, synthesized, and evaluated for their biological activity. Among them, IC 50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a‐18 and 3b‐1 were 0.58 and 0.44 μM for human serum butyrylcholinesterase ( h BuChE), respectively, and both of them exhibited more than 30‐fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of h BuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent β‐amyloid (Aβ) self‐aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood–brain barrier permeation assay, compounds 3a‐18 and 3b‐1 showed enough blood–brain barrier permeability. In drug‐likeness prediction, compounds 3a‐18 and 3b‐1 showed good gastrointestinal absorption and a low risk of human ether‐a‐go‐go‐related gene toxicity. Therefore, compounds 3a‐18 and 3b‐1 are potential multitarget anti‐AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for h BuChE as well as prevent Aβ self‐aggregation.