Aim: The aim of this study was to evaluate the in vitro effect of coumarin and 15 monosubstituted
derivatives on the inhibition of human platelet aggregation induced by various proaggregatory
agonists, particularly by epinephrine.
Background: The emergence of residual platelet reactivity during the use of conventional antiplatelet
agents (acetylsalicylic acid and clopidogrel) is one of the main causes of double therapy´s
therapeutic failure. Platelet adrenoceptors participate in residual platelet reactivity. Therefore, it is
necessary to develop new antiplatelet agents that inhibit epinephrine-induced platelet aggregation
as a new therapeutic strategy. Information on the antiplatelet activity of coumarins in inhibiting
epinephrine-induced aggregation is limited.
Objective: The objective of this study was to establish the structure-activity relationship (SAR) of
coumarin derivatives with hydroxy, methoxy, and acetoxy groups in different positions of the coumarin
nucleus to identify the most active molecules. Moreover, this study aimed to use in silico
studies to suggest potential drug targets to which the molecules bind to produce antiplatelet effects.
Methods: The platelet aggregation was performed using a Lumi-aggregometer; the inhibitory activity
of 16 compounds were evaluated by inducing the aggregation of human platelets (250 × 103/μl)
with epinephrine (10 μM), collagen (2 μg/ml) or ADP (10 μM). The aggregation of control
platelets was considered 100% of the response for each pro-aggregatory agonist.
Results: Eleven molecules inhibited epinephrine-induced aggregation, with 3-acetoxycoumarin
and 7-methoxycoumarin being the most active. Only coumarin inhibited collagen-induced platelet
aggregation, but no molecule showed activity when using ADP as an inducer.
Conclusions: In silico studies suggest that most active molecules might have antagonistic interactions
in the α2 and β2 adrenoceptors. The antiplatelet actions of these coumarins have the potential
to reduce residual platelet reactivity and thus contribute to the development of future treatments for
patients who do not respond adequately to conventional agents.