Abstract

The development of new antiplatelet agents is essential due to the limitations of existing therapies and the high prevalence of thrombotic disorders. As part of a project aimed at harnessing multicomponent-assisted synthetic strategies for drug discovery, we identified a novel class of potent antiplatelet compounds. Herein we report the design, synthesis, and pharmacological evaluation of a new series of N-substituted-2-((arylethyl)amino)-2-(2-methoxyphenyl)acetamides, along with structure-activity relationship analysis and a preliminary investigation of their mechanism of action. The most active compounds, 7d, 9e, and 6f, exhibited IC?? values of 0.92 ± 0.24, 0.59 ± 0.10, and 0.39 ± 0.07 µM, respectively, in serotonin (30 µM) plus collagen (1 µg/mL)-induced platelet aggregation assays, outperforming sarpogrelate (IC?? 5.41 ± 1.25). Functional and binding studies confirmed that these compounds act as low-affinity, weak partial agonists at 5-HT2A, suggesting their antiplatelet effects arise from serotonin-dependent pathways rather than direct 5-HT2A receptor antagonism. Additional experiments confirmed that the selected compounds are non-cytotoxic and significantly suppress P-selectin expression and CD63 secretion, demonstrating inhibition of both early and late stages of platelet activation. These findings introduce a new mechanistic approach to platelet inhibition, expanding the chemical space for antiplatelet drug development. Further studies should focus on molecular target identification and combination therapy potential for thrombosis treatment. © 2025 The Authors