Non‐peptide‐based new class of platelet aggregation inhibitors: Design, synthesis, bioevaluation, SAR, and in silico studies

A series of 2‐oxo‐2‐phenylethylidene linked 2‐oxo‐benzo[1,4]oxazine analogues 17a–x and 18a–o , incorporated with a variety of electron‐withdrawing as well as electron‐donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a–x and 18a–o were evaluated for their arachidonic acid (AA)‐induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC 50 = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i , 17x , 18f , 18g , 18h , 18i , 18l , and 18o , were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T 3 fibroblast cell lines by MTT assay of the promising compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were also performed and the compounds were found to be non‐toxic in nature. Furthermore, the results on the AA‐induced platelet aggregation inhibitory activities of these compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non‐peptide‐based functionalized 2‐oxo‐benzo[1,4]oxazines as platelet aggregation inhibitors.