Design,Synthesis And Biological Activity Evaluation Of Acetaminobenzene Sulfonamide Derivatives

Sulfonamide compounds are a very important class of compounds in synthetic chemistry and medicinal chemistry.The sulfonamide group constitutes a variety of drugs with anti-microbial,anti-tumor,anti-inflammatory,hypoglycemic,anti-psychotic,anti-cancer and protease inhibitory activities.The discovery of the first sulfonamide drug Prontosil opened a new era in medicine,and more and more researchers are committed to the development and screening of sulfonamide drugs.In this paper,a series of sulfonamide compounds have been synthesized.The inhibitory effect of the compounds on carbonic anhydraseⅡ（CAⅡ）and acetyl cholinesterase and the structure-activity relationship were predicted through molecular docking studies.In vitro experiments were used to evaluate the carbonic anhydraseⅡinhibitory activity and acetyl cholinesterase inhibitory activity of the compounds.In addition,the antibacterial activity and the activity of inhibiting the growth of lung cancer cells and breast cancer cells of the compounds were also evaluated.The main contents are as follows:（1）Acetaminobenzene sulfonyl chloride and p-hydrazinobenzene sulfonamide reacted with a variety of compounds containing amino groups,halogens and carbonyl groups to synthesize a series of sulfonamide compounds.The purity of the compounds were characterized by high performance liquid chromatography（HPLC）.The structure of the compounds were characterized and confirmed by proton nuclear magnetic resonance spectroscopy（¹H-NMR）.（2）The compounds were molecularly docked with carbonic anhydrase Ⅱ and acetyl cholinesterase by MOE 2015.10 software.Compounds 1b,1e,2b,and 3a were stable in combination with carbonic anhydrase Ⅱ and formed more hydrogen bonds with amino acid residues in the active site of the enzyme.Compounds 1e,2a,2b,and3c were stable in combination with acetyl cholinesterase and formed more hydrogen bonds with amino acid residues in the active site of the enzyme.（3）The inhibitory activity of the compounds on carbonic anhydraseⅡwas determined by esterase method.Compounds 1b,1e,2a,2b,3a and 3c have higher inhibitory activity against CAⅡ.The IC₅₀ values of these six compounds are better than or close to the positive control drug acetazolamide,showing excellent inhibitory activity against CAⅡ.（4）The inhibitory activity of the compounds on acetyl cholinesterase was determined by Elman’s method.Compounds 1e,2a,2b,and 3c have higher inhibitory activity on acetyl cholinesterase.The IC₅₀ values of these four compounds are close to the positive control drug donepezil.（5）The inhibitory activity of the compounds against the seven commonly used evaluation strains stipulated in the 2020 edition of the Pharmacopoeia of the People’s Republic of China was determined by the oxford cup method.The seven bacteria are E.coli,S.aureus,P.aeruginosa,B.subtilis,S.typ Hi,C.albicans and A.niger.By observing the minimum inhibitory concentration（MIC）,it was screened out that compounds 1a and 3b had lower MIC values and higher antibacterial activities against the 7 tested strains.（6）The cell survival rate of the compounds against A549 lung cancer cells and231 breast cancer cells was determined by MTT method.Compounds 1a,1b,1c,1e,3a,3b,and 3c treated A549 lung cancer cells with a lower cell survival rate.These compounds well inhibited the proliferation of A549 lung cancer cells.Compounds 1a,1b,1e,2a,2c,3a,3c treated 231 breast cancer cells with lower cell survival rate,these compounds can well inhibit the proliferation of 231 breast cancer cells.The ability of the compounds to promote cell apoptosis was evaluated by TUNEL analysis,and the proportion of apoptotic cells in the cells treated with compound 3a was higher.The effect of the compounds on the mitochondrial membrane potential was detected by the JC-1 staining method.Compounds 3a,1c,and 1e have a certain effect on promoting mitochondrial depolarization of lung cancer cells.