Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease

• DOI: 10.1016/j.ejmech.2019.05.062
• Publication Date: 2019-05-28T04:24:31Z
• Authors: Rosa Purgatorio; Modesto de Candia; Marco Catto; Antonio Carrieri; Leonardo Pisani; Annalisa De Palma; Maddalena Toma; Olga A. Ivanova; Leonid G. Voskres...; Cosimo D. Altomare
• Keywords: 570; Indoles; 610; Structure-Activity Relationship; 03 medical and health sciences; Catalytic Domain; Cell Line, Tumor; Azepino[4,3-b]indole; Humans; 0303 health sciences; Amyloid beta-Peptides; Dose-Response Relationship, Drug; Molecular Structure; Azepines; Free Radical Scavengers; Alzheimer's disease; Neuroprotection; Peptide Fragments; 3. Good health; Molecular Docking Simulation; Neuroprotective Agents; Butyrylcholinesterase; Drug Design; Acetylcholinesterase; Amyloid-β aggregation; Cholinesterase Inhibitors; Protein Multimerization; Protein Binding

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 μM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aβ1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.