Synthesis Of 4-ethoxy-N,N’-Two(Halogenatedphenyl)Isophthalamides Derivatives Anti-platelet Aggregat Activity

This subject is to search for the better anti-platelet drugs. Based on the previous works of4-methoxyisophthalamides derivatives in our laboratory and following the principle of bioisosterism, with 4- methoxyl-isophthalamides as a leading compound we transformed the chemical structure of 4-methoxyl-isophthalamides by replacing the two different phenamino groups with two anilino groups. Total seventeen target 4-ethoxy isophthalamides were designed and synthesized and All compounds were characterized on the basis of MS, IR and1 HNMR methods, whose melting points were also determined. Each of them have not been reported before.A total of seventeen compounds were enrolled in this study. The in vitro activity studies on anti-platelet aggregation of each target compounds have been done by the Born test and the results shows that of which, PN523 has the highest activity, and five compounds PN518,PN520, PN521, PN523 and PN525 showde higher activities than that of the Picotamide,Slightly worse than aspirin, while compound PN521, PN523, PN525 exhibited the lower IC50 value,whose pharmacological activity superior to both aspirin and Picotamide. Compound PN518 and PN520 exhibited the lower IC50 than picotamide; show that compound PN518,PN52 and PN525 superior to aspirin and picotamide both as the positive control drugs in the test of inducing platelet aggregation test by the Collagen. Compound PN518 have the best inhibitory effect than aspirin and picotamide and compound PN521 the inhibitory effect superior to picotamide but less than aspirin in the test of inducing platelet aggregation by the Arachidonic acid.The compounds PN518,PN520,PN521,PN523 and PN525 which exhibited the strongest in vitro anti-platelet aggregation activities were selected to test the acute toxicity in mice and the results show that compounds PN518,PN523 and PN525 bear no significant risk of acute toxicity,superior to both aspirin and picotamide, and that compound PN520, PN521 is only significantly toxic at very high doses.The compounds PN518, PN520, PN521, PN523 and PN525 which exhibited more stronger than Picotamide in vitro anti-platelet aggregation activities and good performance in the acute toxicity and were selected to do the tests of cytotoxicity effect on L-929 cells. Further With picotamide as the positive control drugs.Cytotoxicity effect on L-929 cells tests, five target compounds PN518, PN520, PN521,PN523 and PN525 have been done. And the results from these experiments revealed that compounds PN518 exhibit higher activities in vitro activity than the picotamide and PN518 exhibits the lowest acute toxicity and cytotoxicity.In the end, according to pharmacology results, the structure activity relationship(SAR) of target compounds were summarized. These results provide important references for future research in our laboratory.