Design, Synthesis, And Evaluation Of Novel Coumarin Derivatives As Anti-platelet Agents

Cardiovascular disease is a major cause of human morbidity and mortality worldwild. The results show that the Cardio and cerebrovascular diseases are related with thrombosis due to Platelet abnormal aggregation. Therefore, anti-platelet aggregation drugs play an important role in cardiovascular disease. Current antiplatelet drugs, such as aspirin(ASP) and ticlopidine, are used to protect against thrombosis and reduce the risk of myocardial infarction, ischaemic stroke, vascular disease and cardiovascular fatal events. However, current antiplatelet drugs have certain disadvantages such as notable side effects and inefficient therapy. For example,ASP may cause stomach ulcers and bleeding while ticlopidine lead to indigestion and diarrhoea. Therefore, development of new antiplatelet drugs with more effectivity and fewer side effects will be of great significance for the treatment of cardiovascular diseases.Coumarins(benzopyran-2-one) are a large family of compounds of both natural and synthetic origin and displayed extensive biological activities, such as antioxidant,anticoagulant, antihyperglycemic and antitumor, etc. Moreover, coumarin possess low cytotoxicity and excellent cell permeability, and have a relatively low molecular weight suitable for modification. Hence coumarins have attracted much attention in drug research. It has been reported that coumarins of natural and synthetic origin obviously inhibit platelet aggregation leaded by many inducers and own potential medical value. Hence,in an effort to develop novel and potent antiplatelet agents, the paper will modify and optimize basic structure of coumarin.First, coumarin-3-carboxylic acid was synthesized by Knoevenagel reaction using salicylaldehyde as raw material. In addition, 4-Methylumbelliferone was synthesized using resorcino as raw material through pechmann reaction. Then, nicotinic acid-coumarin hybrids and aspirin-coumarin hybrids were designed utilizing combination principle. Two series of target compounds were synthesized and their structures were confirmed by IR, EIS-MS, 1H-NMR.The novel coumarin derivatives were evaluated by inhibition of platelet aggregation in rabbit platelet rich plasma(PRP) in response to ADP(10 μM) using Born’s turbidimetric method. The result indicated all target compounds possessed antiplatelet activity, especially I1-I5, II3, II6 had potent antiplatelet activities compared with aspirin. Analysis of SAR revealed that the antiplatelet aggregation activity of the target compounds were relative with the length of linker of carbon chain. Variation in the length of carbon chain affected significantly the antiplatelet aggregation activity of these derivatives. For example, compounds with two-carbon chain displayed stronger antiplatelet aggregation activity. What’s more, the nicotinic acid derivatives exhibited much stronger antiplatelet aggregation activity than those which containing the aspirin moiety, especially substituent at C-3 position of coumarin. The further research remains to be investigated.