Synthesis, biological and computational evaluation of benzoxazole hybrid analogs as potential anti-Alzheimer's agents
Creators: name: Othman, Mohamed S
name: Hussain, Rafaqat
name: Rahim, Fazal
name: Ullah, Hayat
name: Khan, Shoaib
name: Taha, Muhammad
name: Fareid, Mohamed A
name: Altaleb, Anas T
name: Aboelnaga, Shimaa M
name: Shah, Syed Adnan Ali
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Neuroscience
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: FOS: Biological sciences
subject: Cancer
subject: Mental Health

description: <b>Aim:</b> Current study aims exploration of <i>bis</i>-benzoxazole bearing <i>bis</i>-Schiff base scaffolds (<b>1–16</b>) as anti-Alzheimer's agents. <b>Materials &amp; methods:</b> 2-aminophenol is used as starting materials which react with different reagents in different step to give us <i>bis</i>-benzoxazole bearing <i>bis</i>-Schiff base analogs. NMR and HREI-MS techniques were used for characterization. All derivatives demonstrated varied range of activities with IC<sub>50</sub> 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-<b>3</b> was found most potent. Molecular docking explored modes of interactions between scaffolds and receptor sites of targeted enzymes. <b>Conclusion:</b> 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 (CS<sub>2</sub>), 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 (<b>IV</b>) and 2-(benzo[d]oxazol-2-ylthio)-1-(3-nitrophenyl)ethan-1-onewere mixed to obtain <i>bis</i>-benzoxazole-based <i>bis</i>-Schiff base derivatives (<b>1–16</b>). The newly afforded <i>bis</i>-benzoxazole derivatives (<b>1–16</b>) 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 IC<sub>50</sub> 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.