Synthesis And Evaluation Of Benzenesulfonamide Hdroxamic Acid Analogs Urease Inhibitors

Helcobacter pylori is potentially dangerous to people all over the world.Infection with HP will cause various gastrointestinal diseases and even other system diseases,such as nervous system,blood system,cardiovascular system and so on.Studies have shown that urease is the main virulence factor of Helcobacter pylori.Therefore,urease inhibitors are regarded as the first choice for the treatment of related diseases.In this paper,a series of 41 benzenesulfonyl chloride aminohydroxamic acids were synthesized by acylation,N-alkylation and oximation with substituted aniline and4-tert-butyl benzene sulfonyl chloride as the main substrates.The enzyme inhibitory activity of the obtained compounds were tested,and three compounds with better inhibitory activity were obtained,c39,c40 and c41,IC₅₀was（0.095±0.02）μM,（1.35±0.05）μM and（0.13±0.09）μM respectively.Compare with the positive control acetylhydroxamic acid,the inhibitory activities of the three were higher than those of the positive control.It was found that the introduction of strong electron withdrawing groups in the benzene ring was beneficial to improve the enzyme inhibitory activity of the compounds.The selected compounds were analyzed by Surface Plasmon Resonance.The results showed that the compounds c39,c40 and c41 had good binding ability with urease,KD value was c39（3.43±0.21）×10^-4μM,c40（6.67±0.61）×10^-4μM and c41（5.48±0.42）×10^-4μM.The three compounds c39、c40 and c41 were tested for enzyme kinetics,and the obtained data were collected,sorted and analyzed to obtain their corresponding values of K_iand K_i’were obtained.The Ki values of the three compounds are（0.71±1.01）μM,（1.32±0.31）μM and（1.01±0.57）μM,and Ki’are（4.53±2.14）μM,（3.24±0.91）μM and（4.20±0.79）μM respectively.The comprehensive comparison shows that the inhibition type of these compounds belongs to the slow,reversible,mixed competition mechanism.Through molecular docking,it was found that the hydroxamic acid structure,carbonyl group,sulfonyl group,methyiene group and benzene ring structure of c39,c40and c41 played an important role in the binding process of urease.The tert butyl group in compounds c39 has a hydrophobic interaction with the surrounding amino acid residues,while the intermolecular force formed by bromine,fluroine atoms in compounds c40 and c41 and the surrounding amino acid residues is not as strong as that of tert butyl group.The data obtained by SPR method and molecular docking confirmed the results of enzyme activity inhibition experiment,namely c39>c41>c40.