Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β-Secretase Enzymatic Activity Involved in Alzheimer’s Disease
Proteases BACE1 (β-secretases) enzymes have been recognized as a promising target associated with Alzheimer’s disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on vi...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2020-01-01
|
| Series: | BioMed Research International |
| Online Access: | http://dx.doi.org/10.1155/2020/8934289 |
| Summary: | Proteases BACE1 (β-secretases) enzymes have been recognized as a promising target associated with Alzheimer’s disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on virtual screening, thirteen different compounds were synthesized and subsequently evaluated via in vitro and in vivo studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC50=97±0.91 nM) and active to arrest (99%) β-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (p<0.05). Improved pharmacokinetic parameters, viz., Log Po/w (1.76), Log S (-2.73), and better penetration to the brain (BBB permeation) with zero Lipinski violation, made it possible to hit the BACE1 as a potential therapeutic source for AD. |
|---|---|
| ISSN: | 2314-6133 2314-6141 |