Modify Structure Of Vanillic Acid And Study On Its Derivatives' Pharmacological Activities

Blumea riparia(BI)DC is a traditional Chinese herbal medicine,which has significant effect on gynecological diseases.Vanillic acid is one of active ingredient extracted from Blumea riparia(Bl)DC.In this thesis vanillic acid as the raw material attached to sulfanilamides to synthesize 21 amide derivatives with novel structure.The target compounds' structures had been confirmed by IR,NMR and MS.Through blood coagulation activity test,the four indicators in blood coagulation of the products had no statistical difference compared with blank groups at lower concentration(c=0.06 mg·mL-1 and c=0.12 mg·mL-1).TT(thrombin time)values of a few products decreased or increased significantly compared with blank groups while c=0.24 mg·mL-1.Zxp-2 and Zxp-7 possessed slight coagulation activity;Zxp-4 showed a certain degree of anticoagulant activity;TT values of Zxp-10 and Zxp-16 appeared obvious change compared to the blank groups without statistical difference.Isolated uterine contraction experiment in vitro is a common way to discover new gynecological drugs.Through this experiment the average inhibition rate of some products did not change obviously compared to blank groups to be found.The data of 13 products was statistically significant and the change rate was above 10%.All products had effect on the isolated uterine contraction frequency and mean contraction force to some extent.Zxp-1 had the strongest inhibition effect on uterine mean contraction force(-17.56%),and Zxp-5 showed the strongest contraction frequency inhibition in vitro uterine(-17.14%),while Zxp-15 possessed inhibiton effect on mean contraction force and contraction frequency,-11.15%and-14.78%separately,which can be used as the reference of looking for dysmenorrhea drugs.Zxp-21 can both promote significantly mean cotraction force and contraction frequency on isolated uterine,+14.72%and+11.67%respectively,which will be beneficial to postpartum uterine recovery and able to prevent postpartum hemorrhage,meanwhile this can guide to synthesize dysfunctional uterine bleeding drugs.In the antibacterial experiment,there were seven products having inhibition effect.Zxp-2 showed better effect than other products with minimal inhibitory concentration(MIC)0.625 and 2.5(mg·mL-1)to shigella dysenteriae and staphylococcus aureus respectively.Followed by Zxp-17,MIC was 1.25(mg·mL-1)to the chicken pullorosis,meanwhile the rest of the MIC was between 5-10(mg·mL-1).The interaction mechanism between the 19 products and bovine serum albumin(BSA)was studied by fluorescence quenching method under simulated physiological conditions.The results showed that interaction behavior existed between them,and the fluorescence quenching mechanism for BSA through all products was likely static quenching process predominately.In addition to Zxp-16,all products with BSA had one binding site which can form complexes with BSA(1:1).Most of the products' binding constants Ka were higher than 104 order of magnitude which can be storaged,distributed,metabolized and transported by protein,indicating a strong binding capacity to BSA.Zxp-16 had the highest Ka,Ka=1.24×107 L·mol-1(301K)with n=1.51,that meant Zxp-16 could likely produce a new complex with BSA at a constant rate of 1:2;Zxp-2 had the lowest Ka,Ka=9.00×102L·mol-1(301K)which had the weakest capacity to combine with BSA.The process of all bindings with BSA was spontaneous based on nonradiaton energy transfer mechanism.Interaction force between products and BSA was hydrophobic interaction,van der Waals and hydrogen bonding mainly,only Zxp5-BSA was formed through electrostatic interactions.The binding sites between products and BSA were closer to the tryptophan residues.The majority of products did not change the conformation of BSA,but Zxp-7,Zxp-9,Zxp-15,Zxp-16,Zxp-17,Zxp-18 and Zxp-19,through the synchronous fluorescence appeared slight red shift or blue shift at ??=15 nm or??=60 nm,which means the BSA conformation had changed in the presense of them.