Rational Design, Synthesis, and Biological Activity of N‐(1,4‐Benzoxazinone)Acetamide Derivatives as Potent Platelet Aggregation Inhibitors

Abstract

Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Platelet aggregation activated by thrombin may have close relationship with thrombosis. Based on our studies on the pharmacophoric role of 1,4‐benzoxazine‐3(4H)‐one for desirable platelet aggregation inhibitory activity, we identified N‐(4‐ethyl‐3‐oxo‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐7‐yl)‐2‐(4‐methylpiperazin‐1‐yl)acetamide (BOAP‐AM6) and N‐(4‐butyl‐3‐oxo‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐7‐yl)‐2‐(4‐(4‐fluorophenyl)piperazin‐1‐yl)acetamide (BOAP‐AM21) as platelet aggregation inhibitors with an IC50 of 8.93 and 8.67 μM, respectively, as potent as the positive control aspirin. A combination of structure–activity relationships studies and molecular modeling revealed that the molecule BOAP‐AM6 interacted with the amino acid residue TYR166 and ARG214 in the binding site of GPIIb/IIIa receptor through hydrogen bond and compound BOAP‐AM21 acted on the amino acid residue ASN215 and ALA218, both through the same approach as the reported potent molecules 7a and 7b.