Design,Synthesis And Evaluation Of ?-aryl Hydroxamic Acids Urease Inhibitors Analogs

Helicobacter pylori?Hp? infection leads to multiple diseases.So urease is the key pathogenic factor of Hp,which has become the treatment of Hp infection caused by gastrointestinal diseases,an important target,urease inhibitors may develop into the future treatment of gastric ulcer and duodenal ulcer and other gastrointestinal diseases preferred drug.Based on the flavonoids tricyclic skeleton as the lead compound,through the similar changes of the tricyclic skeleton structure fitting flavonoids.Isosterism principle structure-activity structure omega and tricyclic equivalent aryl hydroxamic acid urease inhibitor on the basis of the previous work of our group on the four series a total of 76 aniline and phenol hydroxamic acid compounds synthesis and study of urease inhibitory activity.In the synthesis of some of the compounds,and get 7 very good activity compounds,through the mechanism and molecular docking to further clarify its binding with the large molecules of urease.The activity of experiment,aniline hydroxamic acid series a13,c3,c5,c8 and c14 five superior activity compounds,IC₅₀ were?0.44 ± 0.13??mol/L,?0.42 ± 0.14??mol/L,?0.15 ± 0.02??mol/L,?0.22 ± 0.01??mol/L,?0.12 ± 0.07??mol/L,the activity of AHA is significantly better than the control group,AHA?17 ± 1.2??mol/L 140 times;phenol hydroxamic acid d7,d10 series of two excellent activity compounds,IC₅₀ were?0.77 ± 0.13??mol/L,?0.70 ± 0.03??mol/L activity is 25 times that of AHA.The whole cell activity in HP cells,a13,c3,c5,c8,c14,d7 and d10 IC₅₀ respectively?41.97 ± 3.54??mol/L,?16.59 ± 0.45??mol/L,?17.93 ± 0.32??mol/L,?7.91 ± 0.14??mol/L,?8.23 ± 0.12??mol/L,?43.98 ± 3.35??mol/L activity,significantly better than the control AHA?672 ± 25?mol/L,the highest activity was 76 times as much as AHA.The kinetic study confirmed by Michaelis equation fitting showed that 7 compounds were mixed type urease inhibitor,and successfully obtained Ki and Ki',and in accordance with the theory of Ki is less than or equal to IC₅₀.With the further interpretation of molecular docking model compounds and urease molecules,hydroxamic acid part of urease activity fully into the cavity and the active sites of two nickel atoms and residues around the active combination part in activity of benzene ring cavity top,through a combination of hydrophobic and active cavity active residues,the molecular and molecular combination of urease in order to inhibit the activity of urea,into the cavity and combined with the active site.The ?-aryl hydroxamic acid series,aniline and phenol-propionyl hydroxamate activity than that of aniline and phenol acetohydroxamic acid,this shows that in the extension of the carbon chain may lead to enhanced activity,so further research is still in the research group,the compound a13,c3,c5,c8,c14,d7 and d10 is the compound having excellent urease inhibitory activity,and are worthy of in-depth study.