Synthesis And Pharmacological Study Of(6-Methyl)-4-Methoxy/Ethoxy-1,3-Benzenedisulfonamides & Derivatives

In modern society,due to people’s stressful life,fast pace and more serious environmental pollution,the threat to life and health of cardiovascular and cerebrovascular diseases is increasing.Antithrombotic drugs is one of the most important method of treating such diseases at present.With the development of scientific research,such drugs which have been used in clinical medicine have gradually exposed some limitations and drawbacks.Therefore,researches of new antithrombotic drugs which are higher active and less toxic become an important task for pharmaceutical crews and are significant for improving people’s overall health and promoting social development.In this paper,based on the structural modification of the classic antiplatelet aggregation drug picotamide and the retention of the 1,3,4-trisubstituted characteristics of the parent,17 target compounds(Number:PN950-PN966)which were not reported in the literature were designed and synthesized according to the principle of isosterism.They included 9 compounds with the structure of(6-methyl)-4-methoxy-1,3-benzenedisulfonamides and 8 compounds with the structure of 4-ethoxy-1,3-benzenedisulfonamides,hydrazone and hydrazide.The chemical structures of each target compound were confirmed by 1H NMR,13C NMR,ESI-MS and IR spectrums.Aspirin and picotamide were used as positive control drugs,adenosine diphosphate(ADP)and arachidonic acid(AA)were used as inducers,Born turbidimetry was used to screen out the in vitro antiplatelet aggregation activities of new compounds.Through researches,it was found that when ADP was selected as the inducer,the target compounds PN951 and PN952 were more active than control drugs aspirin and picotamide at the same time,the compound PN963 was more active than aspirin and slightly less active than picotamide.The IC50 values of the above three compounds were lower than those of the control drugs.When AA was selected as the inducer,the target compounds PN956 and PN957 were more active than aspirin and picotamide at the same time,the compound PN962 was more active than aspirin and slightly less active than picotamide.The IC50 value of the compound PN956 was higher than that of picotamide and lower than aspirin,the other two compounds were lower than those of the control drugs.Refer to the results of in vitro antiplatelet aggregation activities,top 6 active compounds PN951,PN952,PN956,PN957,PN962 and PN963 were selected for in vitro cytotoxicity study and compared with the positive control drug picotamide.The test results exhibited that the cytotoxicity was proportional to the concentration of the drug,and when the concentration was high,the cytotoxicity was sharply increased.Among them,4 compounds PN951,PN952,PN956 and PN957 were less toxic than picotamide at 10 μmol/L,3 compounds PN951,PN956 and PN957 were less toxic than picotamide at 20 μmol/L,only the compound PN951 was less toxic than picotamide at 40 μmol/L and 80 μmol/L.Through the in vitro antiplatelet aggregation activitiy test of 17 target compounds and the in vitro cytotoxicity study of 6 highly active compounds,it was found that the compound PN951 had both high activity and low toxicity,as a result,it has further in-depth research value.According to the structural characteristics of the lead compound picotamide,84-methoxy(ethoxy)-1,3-benzenedisulfonamides with heterocyclic structure were innovatively synthesized.After a series of subsequent tests,it was found that the activities of these compounds were generally high and the toxicities were low.These scientific research achievements expand the ideas of research and development of antiplatelet aggregation drugs.Future synthetic research directions can be based on the heterocyclic structures,attempt to link different heterocyclic substituents in the side chains,and expand the scope of research constantly to obtain more higher active and less toxic compounds.