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Molecules 2016, 21(5), 676; doi:10.3390/molecules21050676

Synthesis and in Vitro and in Vivo Anticoagulant and Antiplatelet Activities of Amidino- and Non-Amidinobenzamides

1,†
,
2,3,†
,
2,* and 1,*
1
College of Pharmacy, Catholic University of Daegu, Hayang-ro 13-13, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea
2
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea
3
Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 700-422, Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 1 March 2016 / Revised: 3 May 2016 / Accepted: 9 May 2016 / Published: 21 May 2016
(This article belongs to the Section Bioorganic Chemistry)
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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 113, 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. View Full-Text
Keywords: antiplatelet; anticoagulant; aPTT; amidinobenzamide; nonamidinobenzamide antiplatelet; anticoagulant; aPTT; amidinobenzamide; nonamidinobenzamide
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Lee, S.H.; Lee, W.; Bae, J.-S.; Ma, E. Synthesis and in Vitro and in Vivo Anticoagulant and Antiplatelet Activities of Amidino- and Non-Amidinobenzamides. Molecules 2016, 21, 676.

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