Design, synthesis and biological evaluation of novel trimethylpyrazine-2-carbonyloxy-cinnamic acids as potent cardiovascular agents

A series of novel trimethylpyrazine-2-carbonyloxy-cinnamic acids and esters were designed, synthesized and evaluated for their inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation in vitro and also assayed for their protective effect against hydrogen peroxide (H2O2)-induced oxidative damage on Ea.hy926 cells. The results showed that many compounds exhibited high activity in one or both of the assays, of which, compound F′10 displayed the highest protective effect on the proliferation of the damaged Ea.hy926 cells (EC50 = 1.7 μM), presenting almost 40 times higher potency than that of lipoic acid, and compound F3 was the most active anti-platelet aggregation agent with IC50 = 9.6 μM, comparable to that of clopidogrel. The structure–activity relationships of these compounds were also discussed.

[1]  Hua Li,et al.  Protective effects of cinnamic acid and cinnamic aldehyde on isoproterenol-induced acute myocardial ischemia in rats. , 2013, Journal of ethnopharmacology.

[2]  Xiangyu Zhang,et al.  Effects of Ligustrazine on pulmonary damage in rats following scald injury. , 2012, Burns : journal of the International Society for Burn Injuries.

[3]  Hu Peng,et al.  Effects of Ligustrazine on pancreatic and renal damage after scald injury. , 2012, Burns : journal of the International Society for Burn Injuries.

[4]  H. Ozyurt,et al.  Reactive oxygen species and ischemic cerebrovascular disease , 2012, Neurochemistry International.

[5]  J. Hao,et al.  Protective effects of ligustrazine on TNF-α-induced endothelial dysfunction. , 2012, European journal of pharmacology.

[6]  C. Leeuwenburgh,et al.  Redox Balance in the Aging Microcirculation: New Friends, New Foes, and New Clinical Directions , 2012, Microcirculation.

[7]  S. Rhee,et al.  Regulation of reactive oxygen species generation in cell signaling , 2011, Molecules and cells.

[8]  P. Zhan,et al.  Ligustrazine derivatives. Part 5: design, synthesis and biological evaluation of novel ligustrazinyloxy-cinnamic acid derivatives as potent cardiovascular agents. , 2011, European journal of medicinal chemistry.

[9]  M. Obrenovich,et al.  Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases. , 2011, Recent patents on cardiovascular drug discovery.

[10]  G. Oh,et al.  The role of peroxidases in the pathogenesis of atherosclerosis. , 2011, BMB reports.

[11]  B. Coller.  Historical perspective and future directions in platelet research , 2011, Journal of thrombosis and haemostasis : JTH.

[12]  Sheng-fu Li,et al.  The protective mechanism of ligustrazine against renal ischemia/reperfusion injury. , 2011, The Journal of surgical research.

[13]  L. Maeng,et al.  Effect of Combination Therapy with Sodium Ozagrel and Panax Ginseng on Transient Cerebral Ischemia Model in Rats , 2011, Journal of biomedicine & biotechnology.

[14]  T. Münzel,et al.  Is oxidative stress a therapeutic target in cardiovascular disease? , 2010, European heart journal.

[15]  M. Levi,et al.  Platelet-vessel wall interaction in health and disease. , 2010, The Netherlands journal of medicine.

[16]  C. Mathers,et al.  Global and regional causes of death. , 2009, British medical bulletin.

[17]  Wenfang Xu,et al.  Ligustrazine derivatives. Part 3: Design, synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents. , 2009, Bioorganic & medicinal chemistry.

[18]  L. Brass,et al.  Novel Therapeutic Targets at the Platelet Vascular Interface , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[19]  Wenfang Xu,et al.  Design, synthesis, and biological activities of novel Ligustrazine derivatives. , 2007, Bioorganic & medicinal chemistry.

[20]  Zhao-quan Huang,et al.  Protective effects of icariin on human umbilical vein endothelial cell injury induced by H2O2 in vitro. , 2005, Pharmacological research.

[21]  H. Igarashi,et al.  The effect of ozagrel sodium on photochemical thrombosis in rat: therapeutic window and combined therapy with heparin sodium. , 2002, Life sciences.

[22]  A. Kesy,et al.  Microplate reader--a convenient tool in studies of blood coagulation. , 1997, Thrombosis research.

[23]  R J Gould,et al.  Platelet aggregation monitored in a 96 well microplate reader is useful for evaluation of platelet agonists and antagonists. , 1995, Thrombosis research.

[24]  P. Singh,et al.  Cinnamic acid induced changes in reactive oxygen species scavenging enzymes and protein profile in maize (Zea mays L.) plants grown under salt stress , 2012, Physiology and Molecular Biology of Plants.

[25]  Masafumi Ueno,et al.  Role of platelets and antiplatelet therapy in cardiovascular disease. , 2011, Journal of atherosclerosis and thrombosis.

[26]  F. Liao,et al.  Herbs of activating blood circulation to remove blood stasis. , 2000, Clinical hemorheology and microcirculation.

[27]  F. Liao,et al.  Ligustrazine, allicin and shear-induced platelet aggregation. , 2000, Clinical hemorheology and microcirculation.