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

• Published in: Archiv der Pharmazie (Weinheim) Vol. 357; no. 5; pp. e2300603 - n/a
• Main Authors: Zeng, Xianghao, Cheng, Shaobing, Li, Huilan, Yu, Haiyang, Cui, Yushun, Fang, Yuanying, Yang, Shilin, Feng, Yulin
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.05.2024; Wiley Subscription Services, Inc
• Subjects: Acetylcholinesterase - metabolism; ADMET; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; antioxidant; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Binding sites; Blood-Brain Barrier - metabolism; butyrylcholinesterase; Butyrylcholinesterase - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Design; Enzyme kinetics; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; multitarget compound; PC12 Cells; Pharmacology & Pharmacy; Physical Sciences; Rats; Science & Technology; Structure-Activity Relationship; Toxicity; Tryptophan - analogs & derivatives; Tryptophan - chemical synthesis; Tryptophan - chemistry; Tryptophan - pharmacology; tryptophan‐derivative; β‐amyloid aggregation; beta-amyloid aggregation; tryptophan-derivative; antioxidant; butyrylcholinesterase; multitarget compound; ADMET; tryptophan‐derivative; β‐amyloid aggregation
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202300603

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, IC50 (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 (hBuChE), 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 hBuChE. 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 hBuChE as well as prevent Aβ self‐aggregation. Twenty‐seven novel l‐tryptophan derivatives with strong antioxidant potential were designed and synthesized according to the reported  l‐tryptophan derivatives with submicromolar butyrylcholinesterase inhibitory activity. Compounds 3a‐18 and 3b‐1 with the strongest inhibitory activity, also exhibited extraordinary antioxidant activity, inhibitory activity against β‐amyloid1–42 self‐aggregation, and low cell toxicity.