Design, Synthesis And Bioactivity Studies Of Novel Ligustrazine Derivatives

Cardiovascular Diseases (CVDs) are common diseases that seriously threaten people’s health and more than half of the deaths of the world are caused by CVDs. Therefore, the research and development of cardiovascular drugs have become research hot spots in the world.Ligustrazine is an active component of Chinese traditional medicine Chuanxiong (Ligusticum wallichii Franchat). Currently ligutrazine is an important cardiovascular drug for the treatment of coronary atherosclerotic cardiovascular disease and ischemic cerebrocardiac vascular disease. However, Ligustrazine was found inefficient to be applicated in clinical practice because of its moderate activity, rapid metabolism and short half life time, therefore accumulated toxicity often appeared in the patients for keeping an effective plasma concentration by the frequent administration. Thus, it is necessary to develop new generation of the Ligustrazine drugs for treatment of CVDs from molecular modification. Structure-activity relationship studies indicated that pyrazine ring of Ligustrazine might largely be the determinant of its pharmacodynamics, while the substituted groups might primarily govern its pharmacokinetics and toxicity.According to the pharmacokinetic characteristics and oxidative metabolic characteristics in vivo of Ligustrazine, we synthesized3,6-dimethyl-2,5-dioctyl phthalate using two different methods, and made a comparason and discussion on the two methods.According to good activities of metabolites,3,6-dimethyl-2,5-ethyl format was chosed as our lead compound. Based on the analysis of the structures of compound, we designed a series of novel Ligustrazine derivatives. We use the1,3,4-oxadizoles as a isostere of the ester in order to improve its hydrolytic stability. All the newly synthesized compounds have not been reported in literature, and their chemical structures were confirmed by IR,1H NMR and ESI-MS.Activity assays:(1) Anti-platelet aggregation assay:The inhibition of platelet aggregation of the compounds was tested using a newly developed measuring method i.e. microplate-reader-nephelometry. The positive control drug was Ozagrel. The results were as following:several compounds such as B1, B2, B3, B13showed higher inhibitory activity than Ozagrel. Strcture activity relationships were summarized as follows:the compounds with electron withdrawing groups can improve the activity, while there is no relationships between the number of electron withdrawing groups and activity.(2) Protecting vascular endothelial cells against peroxide acute injury assay: These Ligustrazine derivatives have been tested for protecting vascular endothelial cells against hyperoxic acute injury. The viability of injured endothelial cells is assessed by methylthiazolyltetrazolium (MTT) assay. The data shows that most compounds have lower activity than lipoic acid. On the of structure-activity relationships research found that methoxy and methyl might be important to the activity of compounds.In conclusion,19novel Ligustrazine derivatives have been designed and synthesized. The preliminary biological results demonstrated that some Ligustrazine derivatives exihibited better activities than positive control drug, which is significant in developing new generation of the Ligustrazine drugs for treatment of CVDs.