Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine

• Published in: European journal of medicinal chemistry Vol. 81; pp. 15 - 21
• Main Authors: Huang, Guozheng, Kling, Beata, Darras, Fouad H., Heilmann, Jörg, Decker, Michael
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 23.06.2014; Elsevier
• Subjects: Alzheimer's disease; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Butyrylcholinesterase - metabolism; Butyrylcholinesterase inhibitor; Carbamates; Cell Survival - drug effects; Cells, Cultured; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Evodiamine; Humans; Life Sciences & Biomedicine; Molecular Structure; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Pharmacology & Pharmacy; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Science & Technology; Structure-Activity Relationship; Carbamates; Butyrylcholinesterase inhibitor; Neuroprotection; Alzheimer's disease; Evodiamine; ASSAY; CHOLINESTERASE-INHIBITORS; FLUORESCEIN; DERIVATIVES; QUINAZOLINIMINES; PEPTIDE
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2014.05.002

Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a–f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a–f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease. [Display omitted] •The alkaloid evodiamine served as a lead structure for novel butyrylcholinesterase (BChE) inhibitors.•A nanomolar and completely selective BChE inhibitor (11c) was obtained after SARs.•Compound 11c is a highly potent antioxidant and neuroprotectant.