4-Methoxy-3-arylamidobenzamides:Synthesis,Pharmacological Activity And Cell Toxicity

At present,the morbidity and mortality of cardiovascular diseases(CVDs)are increasing year by year.Anti-platelet agents are the mainstay of the treatment and preventing with cardiovascular-associated disease.However,there are still some side effects and limitations to these clinical front-line anti-platelet agents.In addition,many patients are resistant to certain agents,which further increased risk of cardiovascular events.Hence,the development of novel anti-platelet agents with higher activity and lower toxicity is a challenging task for pharmaceutical workers.Picotamide was used as the lead compound in this paper,firstly,we retained the1,3,4-trisubstituted structure characteristics of the parent benzene ring in the molecular structure of Picotamide.Then,according to the splicing principle of drug design and referring to the functional group characteristics of asymmetric amide in the molecular structure of Betrixaban,we took advantage of the amide group in the2’-position of Betrixaban to replace the aminoacyl group in the 3-position of Picotamide.Finally,in order to expand the scope of research and find anti-platelet agents with higher activity,the 3-(aminomethyl)pyridyl group in the 1,3-position side chain of Picotamide was replaced with substituted phenylamino groups.Thirty4-methoxy-3-arylamidobenzamides compounds were designed and synthesized.The in vitro anti-platelet aggregation activities of thirty target compounds were assessed by Born’s method induced by adenosine diphosphate(ADP)and arachidonic acid(AA),respectively.The biological evaluation demonstated that all compounds exhibited certain levels of activities in both of the anti-platelet aggregation assays.Compounds PN920 and PN937 showed stronger activities,and they were superior to those of Picotamide and Aspirin induced by ADP.Compounds PN911,PN928 and PN934 have higher activities than those of Picotamide and Aspirin induced by AA.Fourteen compounds that had better anti-platelet aggregation activities were chosen to cell toxicity test in vitro via CCK-8 assay.The experimental results indicated that those compounds had not obvious cell toxicities at lower drug concentrations.The cell toxicities of those compounds had significantly increased at higher drug concentrations.The cell survival rates of compounds PN911,PN918 and PN937 were superior to that of Picotamide at four specific drug concentrations.In conclusion,compounds PN911 and PN937 exhibited higher anti-platelet aggregation activities and lower cell toxicities,simultaneously.The results displayedthat 4-methoxy-3-arylamidobenzamides have the potential to become a kind of safer and more effective anti-platelet agents with the value of further research.