Synthesis, biological and computational evaluation of benzoxazole hybrid analogs as potential anti-Alzheimer's agents
Aim: Current study aims exploration of bis-benzoxazole bearing bis-Schiff base scaffolds (1–16) as anti-Alzheimer's agents.
Materials & methods: 2-aminophenol is used as starting materials which react with different reagents in different step to give us bis-benzoxazole bearing bis-Schiff base analogs. NMR and HREI-MS techniques were used for characterization. All derivatives demonstrated varied range of activities with IC50 values 1.10 ± 0.40–24.50 ± 0.90 μM against acetylcholinesterase (AChE) and 1.90 ± 0.70–28.60 ± 0.60 μM against butyrylcholinesterase (BuChE) in contrast to donepezil. In both cases, analog-3 was found most potent. Molecular docking explored modes of interactions between scaffolds and receptor sites of targeted enzymes.
Conclusion: This study offering promising approach for optimization and development of potent inhibitors of cholinesterase enzymes.
The complex neurodegenerative disorder is thought to be characterized by behavioral anomalies, progressive cognitive impairment, a range of neuropsychiatric symptoms and limitations on daily activities, named as Alzheimer's disease (AD). 10% of people affected by AD include old age population (Over 65), while the bulk of cases were only identified after the age of 56.
Carbon disulfide (CS2), 2-aminophenol and catalyst (triethylamine) were mixed in acetone to afford 2-marcaptobenzoxazole, which then treated with phenacyl bromide bearing varied substitution to obtain S-substituted benzoxazole. Then, this substrate was dissolved in excess of hydrazine hydrate and acetic acid to afford benzoxazole-based Schiff base intermediate. In the final step, benzoxazole-Schiff base substrate (IV) and 2-(benzo[d]oxazol-2-ylthio)-1-(3-nitrophenyl)ethan-1-onewere mixed to obtain bis-benzoxazole-based bis-Schiff base derivatives (1–16).
The newly afforded bis-benzoxazole derivatives (1–16) demonstrated diverse inhibitory profile with inhibition ranged from 1.10 ± 0.40 to 24.50 ± 2.90 μM (against AChE) and 1.90 ± 0.70 to 28.60 ± 3.60 μM (against BuChE), when compared with donepezil with IC50 values of 2.45 ± 1.50 μM (AChE) and 4.50 ± 2.50 μM (BuChE) respectively. Analog 3, 5 and 7 were recognized as active scaffolds and have leading potential against both enzymes.
For further investigation to evaluate the binding modes of lead candidates (analog 3, 5 and 7) with protein complex, molecular docking was carried out. Results showed that these analogs exhibit promising binding folds with enzymes receptor sites.
