Abstract
Three amidino- and ten non-amidinobenzamides were synthesized as 3-aminobenzoic acid scaffold-based anticoagulant and antiplatelet compounds. The anticoagulant activities of thirteen synthesized compounds 1–13, and 2b and 3b as prodrugs were preliminary evaluated by screening the prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) in vitro. From the aPTT results obtained, two amidinobenzamides, N-(3′-amidinophenyl)-3-(thiophen-2′′-ylcarbonylamino) benzamide (1, 33.2 ± 0.7 s) and N-(4′-amidinophenyl)-3-(thiophen-2′′-ylcarbonylamino) benzamide (2, 43.5 ± 0.6 s) were selected to investigate the further anticoagulant and antiplatelet activities. The aPTT results of 1 (33.2 ± 0.7 s) and 2 (43.5 ± 0.6 s) were compared with heparin (62.5 ± 0.8 s) in vitro at 30 μM. We investigated the effect of 1 and 2 on blood anticoagulant activity (ex vivo) and on tail bleeding time (in vivo) on mice. A tail cutting/bleeding time assay revealed that both 1 and 2 prolonged bleeding time in mice at a dose of 24.1 g/mouse and above. Compounds 1 and 2 dose-dependently inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In addition, 1 and 2 were evaluated on the inhibitory activities of thrombin and FXa as well as the generation of thrombin and FXa in human umbilical vein endothelial cells (HUVECs). Collectively, 1 and 2 possess some antiplatelet and anticoagulant activities and offer a basis for development of a novel antithrombotic product.
Highlights
Thromboembolic diseases are leading causes of cardiovascular-associated morbidity and death [1]
Scheme 1 illustrates the synthesis of amidinobenzamides 1–3
Cellular Viability was performed in human umbilical vein endothelial cells (HUVECs) treated with 1 and 2 for 24 h
Summary
Thromboembolic diseases are leading causes of cardiovascular-associated morbidity and death [1]. Prevention and treatment of arterial thrombosis in patients with cardiovascular diseases (e.g., atherosclerotic vascular disease, acute coronary syndrome) are being achieved using antiplatelet drugs [2], whereas venous thrombosis illness, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are treated with anticoagulant drugs [3,4] Several anticoagulants, such as heparins (unfractionated and low-molecular-weight heparins) and vitamin K antagonists (e.g., warfarin), have proved to be effective in the prevention and treatment of these thrombotic diseases, but considerable shortcomings, such as inconvenient drug administration, unneglectable side effects for heparins, and extensive drug and food interactions. GpIIb/IIIa antagonists [27], ADP inhibitor plus FXa inhibitors [28], and warfarin plus amiodarone [29] Because such combinations may increase the risk of bleeding, these will require careful monitoring in large clinical trials of patients, with particular attention to the elderly [20]. The anticoagulant activities of synthesized compounds on direct thrombin and FXa inhibition, the generation of thrombin, and FXa were evaluated
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