Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives

Christos Kontogiorgis,Orazio Nicolotti,Giuseppe Felice Mangiatordi,Massimiliano Tognolini,Foteini Karalaki,Carmine Giorgio,Alexandros Patsilinakos,Angelo Carotti,Dimitra Hadjipavlou-Litina,Elisabetta Barocelli

doi:10.3109/14756366.2014.995180

Abstract

The interest towards coumarin-based structures stems from their polypharmacological profile. Herein, we present a series of Mannich bases and 7-azomethine-linked coumarin derivatives exhibiting antiplatelet and antithrombotic activities, in addition to the already known anti-inflammatory and antioxidant activities. Among others, compounds 15 and 16 were found to be the most potent and selective inhibitors of platelet aggregation whereas compound 3 also proved to be the most potent in the clot retraction assay. Structure–activity relationship studies were conducted to elucidate the molecular determinants responsible for the herein observed activities. The chance of inhibiting cyclooxygenase-1 was also investigated for evaluating the platelet aggregation induced by arachidonic acid. Taken together, these results suggest that the investigation of other targets connected to the antiplatelet activity, such as phosphodiesterase-3 (PDE3), could be a viable strategy to shed light on the polypharmacological profile of coumarin-based compounds. Docking simulations towards PDE3 were also carried out.

Highlights

Venous and arterial thromboembolic diseases are still the most frequent causes of death1
These results suggest that the investigation of other targets connected to the antiplatelet activity, such as phosphodiesterase-3 (PDE3), could be a viable strategy to shed light on the polypharmacological profile of coumarin-based compounds
All the reagents and chemicals used are of analytical grade and were obtained as follows: adenosine diphosphate (ADP), bovine thrombin (T3399), acetylsalicylic acid (ASA), calf collagen type III, epinephrine bitartrate, sodium citrate, dimethylsulphoxide (DMSO) and Triton were purchased from Sigma Chemical Co

Summary

Introduction

Venous and arterial thromboembolic diseases are still the most frequent causes of death. The second messenger cyclic adenosine monophosphate (cAMP) is a strong platelet activation inhibitor. Antiplatelet agents have been proposed as additional therapeutic tools to prevent thromboembolism through multiple mechanisms of action (ADP receptor antagonists GP(glucoprotein)IIb/IIIa antagonists, phosphodiesterase or cyclo-oxygenase inhibitors). Cilostazol, a PDE3 inhibitor has been proposed as antiplatelet drug endowed with considerable antithrombotic effects in vivo. Cilostamide, Coumarin derivatives comprise a large class of phenolic substances occurring in plants and presenting multiple biological activities. Cilostamide, Coumarin derivatives comprise a large class of phenolic substances occurring in plants and presenting multiple biological activities9–11 Both natural and synthetic derivatives were found to possess significant anti-inflammatory and antioxidant activities and might be potentially used to treat various ailments (cancer, burns and rheumatic diseases). Warfarin, a vitamin K antagonist, was found to play significant role against thromboembolic diseases

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