Hybridization-based design of novel anticholinesterase indanone-carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies
| Autor: | Maryam Hamzeh-Mivehroud, Salar Hemmati, Mohammad Shahrivar-Gargari, Javid Shahbazi Mojarrad, Beyza Ayazgök, Siavoush Dastmalchi, Tuba Tüylü Küçükkılınç |
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| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
medicine.drug_class Chemistry Pharmaceutical Allosteric regulation Pharmaceutical Science 01 natural sciences chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Alzheimer Disease Drug Discovery medicine Animals Horses IC50 Butyrylcholinesterase chemistry.chemical_classification 010405 organic chemistry Acetylcholinesterase 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme chemistry Acetylcholinesterase inhibitor Docking (molecular) Drug Design Electrophorus Indans Carbamates Cholinesterase Inhibitors Pharmacophore |
| Zdroj: | Archiv der PharmazieREFERENCES. 354(7) |
| ISSN: | 1521-4184 |
| Popis: | Inspired by the structures of donepezil and rivastigmine, a novel series of indanone-carbamate hybrids was synthesized using the pharmacophore hybridization-based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC50 values in the micromolar range (compound 4d: IC50 = 3.04 μM; compound 4b: IC50 = 4.64 μM). Moreover, the results of the Aβ1-40 aggregation assay revealed that compound 4b is a potent Aβ1-40 aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype-selective enzyme inhibitors. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multitargeted anti-Alzheimer agents. |
| Databáze: | OpenAIRE |
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