Design, Synthesis And Bioactivity Studies Of Novel Ligustrazine-Chalcone Derivatives

Cerebrocardiac Vascular Diseases (CVDs) are common diseases that seriously threaten people’s health. About12million people’s death are by CVDs according to WTO. In our country, the incidence of the CVDs is growing because of the upgrade of the living standard and the changes of the life style. Also the medicinal treatment enhance the survival of the CVDs greatly, the healing and prognosis of the CVDs are still poor. The research and development of the new kind of cerebrocardiac vascular drugs are still the important strategies for the medical therapy in the world.Atherosclerosis is the pathological basic and the key reason of the ischemia CVDs. The damage of endothelial cell is the common initiating process in the development of atherosclerosis, and the active platelet will eventually lead to the thrombus and finally atherosclerosis. So, the inhibition of platelet aggregation and the protection of the ischemic tissue are the two main approaches for the treatment of ischemia CVDs.Ligustrazine is the main active component of Chinese traditional medicine Ligusticum wallichii Franchat with the chemical structure of tetramethylpyrazine (TMP). Currently it is widely used in the treatment of coronary atherosclerotic cardiovascular disease and other ischemic cerebrocardiac vascular diseases. But, its short half life time and moderate activity limit the use of ligustrazine in clinical. So, the development of the new generation of the ligustrazine derivatives in the treatment of cerebrocardiac vascular diseases is conspicuous. In the structure-activity relationship (SAR) study of TMP we found that:the pyrazine ring of TMP is the pharmacophore which determines its efficacy; while the substituted methyl groups might primarily govern its pharmacokinetics.Chalcone, one kind of flavone with the structure of1,3-diaryl-2-propen-1-ones, is reported to have the activity of relaxing vascular smooth muscle (VSM), anti-platelet aggregation and anti-oxidant, and is efficacy in the treatment of the thrombus and ischemic cerebrocardiac vascular diseases. Thus, we hold the basic skeleton of the chalcone as the structure model, and replace the phenyl group by the ligustrazinyl group according to the principle of hybridization and isostere, which formed the ligustrazine-chalcone derivatives. We hope to acquire the pharmacologically additive or synergetic effects to improve anti-CVDs activity.All the newly synthesized compounds have not been reported in literature, and their chemical structures were confirmed by IR,1H NMR and ESI-MS.Then, we initially determined the activity of the synthesized compounds:(1) Anti-platelet aggregation assay:The anti-platelet aggregation of the compounds was tested using microplate-reader-nephelometry method with clopidogrel and ozagrel as the positive control. The results were as following:Several compounds such as A16, B7, B9, B17showed higher inhibiting activity than Ozagrel with the AIRmax%more than70%. Structure activity relationships were summarized as follows: methoxy group is important for keeping the anti-platelet activity, and the activity when the phenyl B was replaced by ligustrazinyl group is better than that the phenyl A was replaced by ligustrazinyl group.(2) Protecting vascular endothelial cells against hyperoxic acute injury assay: These Ligustrazine derivatives have been tested for protecting EA.hy926cells against hyperoxic acute injury by methylthiazolyltetrazolium(MTT) assay. The biological results demonstrated that compounds A10, All, A20, B13present excellent cerebrocardiac vascular activities with EC50values of30.12μM,18.45μM,37.04uM and26.52μM, respectively, which is2-fold than positive control drug lipoic acid. Structure activity relationships were summarized as follows:methoxy group is important for anti-hyperoxic acute injury in series A, while some compound of series B is showed no anti-hyperoxic acute injury for their toxicity.In conclusion,47novel Ligustrazine-chalcone derivatives have been designed and synthesized. The preliminary biological results have demonstrated that some derivatives have better activities than positive control drug, which is significant in developing new generation of the Ligustrazine drugs for treatment of cerebrocardiac vascular diseases.