New indole derivatives as multitarget anti-Alzheimer's agents: synthesis, biological evaluation and molecular dynamics.
Eman M AzmyIbrahim F NassarMohamed HagrasIten M FawzyMaghawry HegazyMahmoud Mohamed MokhtarAmr Mohamed YehiaNasser S M IsmailWalaa H LashinPublished in: Future medicinal chemistry (2023)
Background: Alzheimer's disease is a neurological disorder that causes brain cells to shrink and die. Aim: Thirteen novel 'oxathiolanyl', 'pyrazolyl' and 'pyrimidinyl' indole derivatives were designed and synthesized as anti-Alzheimer's disease treatment. Method: In vitro enzyme assay was performed against both AChE and BChE enzymes. In addition, antioxidant assay and cytotoxicity on a normal cell line were determined. Molecular docking and dynamic simulations were conducted to confirm the binding mode in both esterases' active sites. In silico absorption, distribution, metabolism, excretion and toxicity studies were also carried out. Results & conclusion: Compounds 5 , 7 and 11 exhibited superior inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with IC 50 values of 0.042 and 3.003 μM, 2.54 and 0.207 μM and 0.052 and 2.529 μM, respectively, compared with donepezil.
Keyphrases
- molecular dynamics
- molecular docking
- cognitive decline
- molecular dynamics simulations
- oxidative stress
- density functional theory
- high throughput
- induced apoptosis
- white matter
- signaling pathway
- cell cycle arrest
- resting state
- mild cognitive impairment
- cerebral ischemia
- dna binding
- cell death
- transcription factor
- blood brain barrier
- endoplasmic reticulum stress
- single cell