| Title | Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Gabr MT, Abdel-Raziq MS |
| Journal | Bioorg Med Chem Lett |
| Volume | 28 |
| Issue | 17 |
| Pagination | 2910-2913 |
| Date Published | 2018 09 15 |
| ISSN | 1464-3405 |
| Keywords | Acetylcholinesterase, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Blood-Brain Barrier, Cell Line, Tumor, Cell Survival, Cholinesterase Inhibitors, Crystallography, X-Ray, Donepezil, Dose-Response Relationship, Drug, Drug Design, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship |
| Abstract | A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC value of 14.7 nM) and BACE-1 inhibition (IC value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied. |
| DOI | 10.1016/j.bmcl.2018.07.019 |
| Alternate Journal | Bioorg Med Chem Lett |
| PubMed ID | 30017317 |
Related Institute:
Molecular Imaging Innovations Institute (MI3)