Synthesis And In Vitro Activities Onanti-platelet Aggregation Of4-Methoxy-1,3-Benzenedicarboxamide Derivatives

In recent years, the incidence of thrombotic diseases increased year by year, for two mainreasons: First, the improvement of living standards; Second, irrational diet, smoking, alcoholconsumption and lack of exercise and other bad habits. Therefore, antiplatelet drugscommonly used as the treatment of thromboembolic disorders have urgent clinical needs andbroad market prospects. The research of new, efficient, low toxicity anti-platelet drugs has ahigh social significance and economic value.Referring to computer-aided drug design model, using the principle of electronics mosaic,Thirteen4-methoxybenzene-1,3-isophthalamides (PN477, PN478, PN479, PN480, PN481,PN482, PN483, PN484, PN485, PN486, PN487, PN488, PN489)were designed andsynthesized with Picotamide as the lead compounds.The structure of the target compounds were confirmed by IR,1H NMR and MS analysis,and also the melting point. The ADP induced platelet aggregation in vitro activity of the13target compounds were assessed by using Born test, the results showed that, compared to thecontrol drugs (Picotamide and Asprin), seven compounds PN477, PN478, PN479, PN480,PN481, PN483and PN484has a better anti-platelet aggregation in vitro activity, higher thanthe positive control drug Picotamide and Asprin, and compounds PN481has the minimumIC50values, which means maximum anti-platelet aggregation activity; the acute toxicity testresults of the seven compounds above showed that six target compounds (PN477, PN478,PN479, PN480, PN481, PN483) had weak overall toxicity, and are worthy of further researchand development; Three lowest acute toxicity compounds (PN478, PN480and PN481) werepicked out to carry L-929cytotoxicity test, the results showed thatthe test substance PN481has4%high cell viability than control drug Picotamide at low doses concentration(10μmol/L), which means it has lower toxicity to the test cells; Even when the concentrationis promoted to a high doses (100μmol/L),although the cell viability of PN478, PN481are alittle bit lower than Picotamide, but still have a high cell viability, worth developing and havehigh research value.Based on the pharmacological test results above, the preliminarystructure-activity relationship of the target compounds was summarized.