Study On The Synthesis And In Vitro Pharmacological Activities & Cytotoxicity Of 4-methoxy/Ethoxy Sulfonamides

Thrombus formation process,the classification of anti-thrombotic drugs and the research on anti-platelet drugs were described in this article.Six 4-methoxy-1,3-benzenedi-sulfonamides and twenty five 4-ethoxy-1,3–benzenedisulfnamides were designed and prepared.And the chmical structures of all the target compound have been confirmed by ESI-MS,IR,¹H NMR,¹³C NMR spectral characterization.On the basis of chemical synthesis,Born turbidimetric method was used to screen the target compounds in vitro against platelet aggregation.Continue to select ten more active target compounds and use L929 cells in vitro toxicity experiments.Based on the pharmacological experimental data,the structure-activity relationship of the target compounds was preliminarily estimated.Anisole was used as the starting material to react with chlorosulfonic acid to form4-meth-oxy-1,3-benzenedisulfonyl chloride,which was reacted with different aromatic amines respectively to generate the target 4-methoxy-1,3-benzenedisulfonamides（PN690-695）.Phenetole as raw material and chlorosulfonic acid to generate the intermediate4-ethoxy-1,3-benzenedisulfonyl chloride,respectively,with different aromatic amines to produce 25 target 4-ethoxy-1,3-benzene disulfonamides（PN696-720）.Another intermediate for the synthesis of the target compound is an aromatic amine.4-Chloro-2-amino-phenetole and 3-fluorobenzylamine were synthesized.Take P-aminophenyl ether as the starting material,through the diazotization,Sandmeyer chlorination,nitration and reduction reaction,4-chloro-2-amino-phenethyl ether was gaven.3-Fluorotoluene as raw material,under the irradiation of bromine and amine reactions,3-fluorobenzylamine was synthesized.Part of related pharmacological studies have been carried out on the target compounds,with clopidogrel,picotamide and aspirin as positive control drugs,respectively,with ADP and arachidonic acid as an inducer,in vitro anti-platelet aggregation activity screening.The results showed that when ADP was used as an inducer,the activity of compound PN720 was higher than that of other compounds except PN703 and PN705.The activities of PN694,PN695,PN697,PN699,PN709,PN715 and PN720 were also higher.Compounds PN720 and PN709are the first and second active two compounds.When arachidonic acid was used as an inducer,the activity of compound PN695 was highest than that of other compounds.Ten compounds PN694,PN695,PN697,PN699,PN706,PN709,PN713,PN715,PN719and PN720 with better activity were selected and tested by MTT assay.The experimental results showed that under the low concentration,these compounds behaved small effect on cells,but large role in high concentrations.Among them,the cell survival rates of the compounds PN695,PN713,PN719 and PN720 at low concentrations were higher than 80%;of which,the survival rate of PN695 cells was higher than that of picotamide.The analysis of pharmacological data showed that the side chain carbon chain increased when n>1,corresponding compounds PN694 and PN695 showed higher activity.In the para and meta-use of two electron withdrawing groups substituted,is conducive to in vitro anti-platelet Aggregation activity increased.Compounds containing a large group at the para-position of the side-chain benzene ring or in the ortho-position show will show lower activity.The compounds PN695 and PN720 have the advantages of high activity and low toxicity and have further research significance.