Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

被引:26
|
作者
Suwanhom, Paptawan [1 ,2 ]
Saetang, Jirakrit [3 ]
Khongkow, Pasarat [4 ]
Nualnoi, Teerapat [5 ]
Tipmanee, Varomyalin [4 ]
Lomlim, Luelak [1 ,2 ]
机构
[1] Prince Songkla Univ, Fac Pharmaceut Sci, Dept Pharmaceut Chem, Hat Yai 90112, Songkhla, Thailand
[2] Prince Songkla Univ, Fac Pharmaceut Sci, Phytomed & Pharmaceut Biotechnol Excellent Ctr PP, Hat Yai 90112, Songkhla, Thailand
[3] Prince Songkla Univ, Dept Surg, Fac Med, Hat Yai 90112, Songkhla, Thailand
[4] Prince Songkla Univ, Dept Biomed Sci & Biomed Engn, Fac Med, Hat Yai 90112, Songkhla, Thailand
[5] Prince Songkla Univ, Fac Pharmaceut Sci, Dept Pharmaceut Technol, Hat Yai 90112, Songkhla, Thailand
来源
MOLECULES | 2021年 / 26卷 / 16期
关键词
quinoxaline; acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; ADME prediction; molecular docking; cytotoxicity; ALZHEIMERS-DISEASE; PERIPHERAL SITE; DOPAMINERGIC-NEURONS; THIOFLAVIN-T; DERIVATIVES; ACHE; BUTYRYLCHOLINESTERASE; QUINAZOLINIMINES; CHOLINESTERASES; SELECTIVITY;
D O I
10.3390/molecules26164895
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 mu M, along with promising predicted drug-likeness and blood-brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 mu M was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.
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页数:18
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