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
| Autor: | Leonardo Pisani, Maddalena Toma, Modesto de Candia, Olga A. Ivanova, Rosa Purgatorio, Cosimo Altomare, Leonid G. Voskressensky, Annalisa De Palma, Antonio Carrieri, Marco Catto |
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| Rok vydání: | 2019 |
| Předmět: |
Indoles
Aché Peptide Pharmacology 01 natural sciences Neuroprotection 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Catalytic Domain Cell Line Tumor Drug Discovery medicine Humans IC50 Butyrylcholinesterase 030304 developmental biology Indole test chemistry.chemical_classification 0303 health sciences Amyloid beta-Peptides Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry General Medicine Azepines Free Radical Scavengers Acetylcholinesterase language.human_language Peptide Fragments 0104 chemical sciences Molecular Docking Simulation Neuroprotective Agents Drug Design language Cholinesterase Inhibitors Protein Multimerization Acetylcholine medicine.drug Protein Binding |
| Zdroj: | European journal of medicinal chemistry. 177 |
| ISSN: | 1768-3254 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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