Development of Benzimidazole Derivatives as Novel Anti-platelet Drugs

Author(s): Wei-Cheng Yao, Lan-Ting Yuan, Wen-Bin Yang, Chih-Hsuan Hsia, Li-Ting Huang, Tzu-Yin Lee, Joen-Rong Sheu, Wan-Jung Lu, Thanasekaran Jayakumar*, Ray-Jade Chen*.

Journal Name: Current Pharmaceutical Biotechnology

Volume 18 , Issue 7 , 2017

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Abstract:

Background: Benzimidazoles are privileged biomolecules which form an integral part of vitamin B12 and have been attracting numerous researchers all over the world to assess their potential therapeutic significance.

Objectives: The comparative in vitro antiplatelet activity of newly synthesized benzimidazole derivatives, M3BIM, C2BIM, and L2BIM in thrombin, adenosine diphosphate (ADP) and epinephrineinduced washed human platelets was investigated.

Method: Reversed-phase silica gel column chromatography, Aggregometry, Flow cytometry and Immunoblotting were used in this study.

Results: M3BIM exhibited a concentration (25-100 µM) dependent inhibitory effect on platelet aggregation induced by thrombin (0.01 U/mL) in washed human platelets and by epinephrine (10 µM) only at a maximum concentration of 500 µM in platelet-rich plasma (PRP); however, C2BIM and L2BIM had no response even at 500 µM against thrombin and 1mM against epinephrine-induced platelet aggregation. Moreover, all these three compounds were not inhibited platelet aggregation induced by ADP (20 µM). Additionally, these compounds showed no effects in thrombin-induced P-selectin expression and αIIbβ3 activation, as evidenced by flow cytometry and clot reaction assays, respectively. Besides, M3BIM (100 µM) significantly abolished thrombin-induced Akt and mitogen-activated protein kinases (MAPKs) phosphorylation; whereas 200 µM C2BIM and L2BIM were not effective on these proteins.

Conclusion: This study affords confirmation for the inhibitory effect of M3BIM in a low dose thrombin and epinephrine-induced platelet aggregation in vitro compared to other imidazole derivatives, C2BIM and L2BIM. These outcomes may recommend that M3BIM can be appraised as a prospective benzeimidazole compound for the treatment of thrombin -induced platelet defect and its related diseases.

Keywords: Platelets, benzimidazole, thrombin, ADP, epinephrine, P-selectin, clot retraction, MAPKs.

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Article Details

VOLUME: 18
ISSUE: 7
Year: 2017
Page: [594 - 605]
Pages: 12
DOI: 10.2174/1389201018666170821113430
Price: $65

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