Design And Synthesis Of Novel Diaryl Sulfonamide Derivatives

Sulfonamide antimicrobials are a class of compounds with a p-aminobenzenesulfonamide structure that are commonly used clinically to prevent and treat microbial infections.In recent years,the development of new sulfonamide compounds has attracted the attention of scientific researchers due to its simple structure,broad antibacterial spectrum and not easy to cause superinfection.Through the modification of its maternal nuclear structure,a variety of clinical sulfonamide antimicrobials have been successfully developed.However,with the use of drugs,the problem of drug resistance has also become more serious.Therefore,it is urgent to create sulfonamide antimicrobials with novel synthetic structures and diversity.In this paper,we uses the principle of molecular assembly,the potential antibacterial activity of diarylmethane fragments can be assembled with structural units such as sulfamethoxazole and sulfadiazine,which are listed on the market.Then a series of new diaryl sulfonamide derivatives were synthesized by Michael addition reaction 1,6-butene.And select p-QMs-sulfamethoxazole series compounds as representatives for in vitro antibacterial activity testing,and preliminarily explore their biological activity.The specific research content is as follows:Firstly,a series of novel diarylsulfonamide derivatives were successfully constructed by using p-methylenequinone（1）and five marketed sulfonamides（2）as substrates and using Michael addition reaction 1,6-butene.Among them,the alkali type,catalyst type and dosage,reaction temperature,solvent and other conditions were investigated,the optimal reaction conditions were determined,and the substrate was expanded,which verified the versatility of the method.Finally,under green solvent-free conditions,Al Cl₃catalyzed the reaction to obtain 32 target compounds with diverse structures（3）,and the structures were confirmed by ¹H NMR and ¹³C NMR spectroscopy.Secondly,to further investigate whether the target compound has biological activity,13 p-QMs sulfamethoxazole series compounds were selected as representatives,Escherichia coli and Staphylococcus aureus were selected as test strains,and the clinical drugs chloramphenicol and norfloxacin were used as positive controls for minimum inhibitory concentration（MIC）testing.The results showed that most compounds had moderate bacteriostatic activity,and the MIC values of compounds 3oa,3la,and 3fa against E.coli were comparable to norfloxacin and twice that of chloramphenicol.Then,using Aotudock 4.0 molecular docking software as a tool,the rigid semi-flexible docking method was adopted to connect with dihydrofolate reductase（PDB:3DRC）molecules using the active molecule 3oa as an example.The results showed that the oxygen atoms of the oxygen atoms in the phenolic hydroxyl group,oxazole ring and sulfonamide group in3oa interacted with the protein amino acid residues through hydrogen bonds,and theoretically analyzed the possible mechanism of compound and bacterial interaction.These results suggest that the introduction of diarylmethane fragments contributes to improving biological activity,and compound（3）is worthy of further study as an antimicrobial candidate.