Synthesis And Biological Activity Evaluation Of Benzenesulfonamides

Sulfonamides are important compounds in pharmaceutical chemistry.Nearly a century after Gerhard Domagk developed the first sulfonamide drug,prontosil,sulfonamides were found to have a variety of pharmacological activities,such as antibacterial,antifungal,antiviral,anticancer,antidepressant,inhibition of carbonic anhydrase,which attracted more and more people to devote themselves to structural optimization and pharmacodynamic research of sulfonamides.In this paper,p-aminobenzenesulfonamide was used as the basic structural unit,and its structure was modified to obtain benzenesulfonamide compounds containing different substituents.Then the antibacterial activity,inhibitory effect on carbonic anhydrase?and cytotoxicity of these compounds were evaluated.Finally,the mechanism of antibacterial and inhibition of carbonic anhydrase II of benzenesulfonamide compounds with different substituents was explored by computer simulation,and the structure-activity relationship of active compounds was discussed.The main contents are as follows:?1?Different benzenesulfonyl chloride compounds were used as starting reactants to synthesize the target compounds with different substituents on the benzene ring by reacting with ammonia or hydrazine hydrate at a ratio of 1:2.The purity of the product was calculated by HPLC,and the structure of the product was characterized by FT-IR and ¹H-NMR.?2?The antibacterial activities of the compounds against Gram-negative bacteria,Gram-positive bacteria and fungi were measured by the cylinder plate method,and the minimum inhibitory concentration and the diameter of the inhibition zone of the compounds against different bacteria were recorded.The results showed that the compounds with substituents of nitro,acetamino and trifluoromethoxy on the benzene ring had lower minimum inhibitory concentration and larger diameter of the inhibition zone,indicating that they had better antibacterial activity.?3?The esterase assay was used to determined the inhibitory effect of the compounds on carbonic anhydrase II.The inhibitory effect of compounds on carbonic anhydrase II was judged by calculating the IC₅₀ values of different compounds for carbonic anhydrase II.The results showed that the IC₅₀ values?4.92?9.83?M?of the compounds with substituents of nitro and acetamino on the benzene ring were all less than the IC₅₀ values?15.68?45.25?M?of the compounds containing methyl,trifluoromethyl and trifluoromethoxy groups.It showed that the benzenesulfonamide compounds with nitro and acetamido substituents on the benzene ring had better inhibitory effect on carbonic anhydrase II than the benzenesulfonamide compounds with methyl,trifluoromethyl and trifluoromethoxy groups on the benzene ring.?4?The MTT method was used to evaluate the cytotoxicity of the active compounds on HepG2 cells and RAW264.7 cells.The results showed that compounds with nitro groups on the benzene ring had greater toxic effect on both cells.?5?The molecular docking of synthetic compounds with dihydrofolate synthase and carbonic anhydrase II was carried out by using AutoDock software.The binding mode of compounds with dihydrofolate synthase and carbonic anhydrase II was explored from the molecular level,and the structure-activity relationship of the compounds on the inhibition of two enzymes was discussed.The results showed that the compounds mainly combined with amino acid residues in the active center of the enzyme through nitro,acetamido,trifluoromethoxy and sulfonyl groups to form hydrogen bonds.In addition,the Molinspiration online program was used to predict the oral bioavailability parameters of synthesized benzenesulfonamide compounds.The results showed that the compounds complied with Lipinski's five rules,indicating that they were promising as oral drugs.