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<p>The aim of this work is the synthesis of nine coumarin-hydrazone derivatives and their characterization by IR, 1D NMR, 2D NMR, NOESY, and elemental analysis, as well as the evaluation of their antiplatelet activity through in vitro and in silico tests. Among the tested series, compounds <b>9</b> and <b>10</b> showed significant inhibition of ADP-induced platelet aggregation, by 87% and 98%, respectively. Notably, compound <b>10</b> completely inhibited arachidonic acid-induced aggregation, while none of the molecules affected the collagen pathway. The selected compounds demonstrate a strong inhibitory effect on platelet adhesion, CD62-P expression, and GPIIb/IIIa activation. Furthermore, molecular docking studies were performed for compounds <b>9</b> and <b>10</b> against the P2Y12 and COX-1 receptors of ADP and arachidonic acid, respectively. The results revealed that both compounds exhibit strong binding affinities (− 8.6 to − 7.9 kcal/mol) for platelet targets and establish interactions with key active site residues. Moreover, in silico ADMET prediction using SwissADME, ProTox-II, and Pred-hERG suggests that the active compounds showed excellent physicochemical and pharmacokinetic properties, low predicted toxicity (LD<sub>50</sub> ≥ 2500 mg/kg), and no risk of cardiotoxicity. Interestingly, in vitro toxicity assessment revealed that they showed no cytotoxic effects on human blood cells, including platelets, erythrocytes, and lymphocytes. The combined in silico and in vitro approach suggests that compounds <b>9</b> and <b>10</b> hold promise as antiplatelet agents with safety profiles, paving the way for further investigation in clinical studies.</p>

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Synthesis and structural characterization of coumarin–hydrazone derivatives as antiplatelet agents: in vitro and in silico evaluation of activity and toxicity

  • 期刊论文

  • 发表日期：

    2025年8月26日

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  • Asma Haffouz,
  • Emna Khdhiri,
  • Ines Dhouib,
  • Ikram Ben Amor,
  • Amira Jerbi,
  • Jalel Gargouri,
  • Emna Sahli,
  • Noureddine Allouche,
  • Ali Gargouri,
  • Gérard Lizard,
  • Souhir Abid,
  • Houcine Ammar,
  • Bassem Khemakhem,
  • Basma HadjKacem

摘要

The aim of this work is the synthesis of nine coumarin-hydrazone derivatives and their characterization by IR, 1D NMR, 2D NMR, NOESY, and elemental analysis, as well as the evaluation of their antiplatelet activity through in vitro and in silico tests. Among the tested series, compounds 9 and 10 showed significant inhibition of ADP-induced platelet aggregation, by 87% and 98%, respectively. Notably, compound 10 completely inhibited arachidonic acid-induced aggregation, while none of the molecules affected the collagen pathway. The selected compounds demonstrate a strong inhibitory effect on platelet adhesion, CD62-P expression, and GPIIb/IIIa activation. Furthermore, molecular docking studies were performed for compounds 9 and 10 against the P2Y12 and COX-1 receptors of ADP and arachidonic acid, respectively. The results revealed that both compounds exhibit strong binding affinities (− 8.6 to − 7.9 kcal/mol) for platelet targets and establish interactions with key active site residues. Moreover, in silico ADMET prediction using SwissADME, ProTox-II, and Pred-hERG suggests that the active compounds showed excellent physicochemical and pharmacokinetic properties, low predicted toxicity (LD50 ≥ 2500 mg/kg), and no risk of cardiotoxicity. Interestingly, in vitro toxicity assessment revealed that they showed no cytotoxic effects on human blood cells, including platelets, erythrocytes, and lymphocytes. The combined in silico and in vitro approach suggests that compounds 9 and 10 hold promise as antiplatelet agents with safety profiles, paving the way for further investigation in clinical studies.