The synthesis of 4,7-disubstituted-2H-benzo[b][1,4]-oxazin-3(4H)-ones using Smiles rearrangement and their in vitro evaluation as platelet aggregation inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2014-03, Vol.24 (6), p.1479-1483
• Main Authors: Xia, Shuai, Liu, Ji-Qiang, Wang, Xiu-Hua, Tian, Ye, Wang, Yu, Wang, Jing-Huan, Fang, Liang, Zuo, Hua
• Format: Article
• Language: English
• Subjects: 4,7-Disubstituted-2H-benzo[b][1,4]oxazin-3(4H)-one; Benzoxazines - chemical synthesis; Benzoxazines - chemistry; Benzoxazines - metabolism; Binding Sites; Catalytic Domain; Molecular docking; Molecular Docking Simulation; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Platelet aggregation; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Protein Binding; Smiles rearrangement; Structure-Activity Relationship; Structure–activity relationships (SAR)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.02.014

A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation inhibitors for structure–activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rearrangement for the preparation of benzoxazine, was proven to be more efficient than the conventional methods. Biological evaluation demonstrated that among all the synthesized compounds, compound 9u (IC50=9.20μM) exhibited the most potent inhibition activity compared with aspirin, the positive control (IC50=7.07μM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well.