1,4-Benzoxazine-3(4H)-ones as potent inhibitors of platelet aggregation: design, synthesis and structure-activity relations.

A series of novel potentially platelet aggregation-inhibiting 1,4-benzoxazine-3(4H)-one derivatives was designed and synthesized through Smiles rearrangement, reduction and acetylation reactions. The antiaggregatory activities of the target molecules on arterial blood samples from rabbits, expressed by IC₅₀ values (μM), were then evaluated in vitro against ADP induced platelet aggregation. The favorable IC₅₀ values of compound 8c (IC₅₀=8.99 µM) and 8d (IC₅₀=8.94 µM) indicated that these two compounds were the most potent molecules among all the synthesized compounds. A detailed molecular docking study to explore the interaction of compounds 8c and 8d with GP IIb/IIIa receptor showed that they these two compounds were docked into the active site of GPIIb/IIIa receptor. These results suggest that the 1,4-benzoxazine-3(4H)-one derivatives are promising lead compounds to develop new platelet aggregation inhibitors.