Synthesis Improvement And Biological Evaluation Of 3-chlorop Henyl-3-hydroxypropionylhydroxamic Acid

About half of the world's population is infected with Hp?Helicobacter pylori?.Hp infection causes gastritis,gastric ulcers,urinary tract stones,nephritis,urinary tract infections,and other diseases.Urease is the main virulence factor,and it is an important target for drugs to anti-gastritis and gastric ulcer.Therefore,urease inhibitors are expected to become first-line drugs for the treatment of various diseases caused by Helicobacter pylori.In this paper,a series of synthesis processes,absolute configuration determination and activity studies of the high activity urease inhibitor 3-?3-chlorophenyl?-3-hydroxy propanoyloxycaproic acid found in the early stage of the research group were carried out.The optimum process conditions obtained by enlarging the synthesis process are:n?3-chlorobenzaldehyde?:n?ethyl ethyl bromide?:n?activated zinc powder?=1:1:2,reaction time 70 min,reaction temperature 43?,the highest yield of compound?B??85%?.n?Compound B?:n?hydroxylamine hydrochloride?:n?sodium methoxide?=1:2:4,reaction time 30 min,the highest yield of compound??±?-CPH??80%?.Chiral resolution of 3-?3-chlorophenyl?-3-hydroxypropanoyloxonate??±?-CPH?,get?S?-CPH,?R?-CPH,they were also studied for their activity and kinetic mechanism.Studies have shown that the urease inhibitory activity IC50 values of?S?-CPH and?R?-CPH are 0.065±0.004?M and 0.093±0.006?M,respectively,and the overall cell activity IC50 valuesof Hp are 0.31±0.02?M and 0.39±0.02?M,respectively.The compound?S?-CPH activity is more than 200 times to the control AHA,and the activity of the compound?R?-CPH is more than 100 times to the AHA.Kinetic studies have shown that compounds?S?-CPH and?R?-CPH are mixed urease inhibitors,with?S?-CPH Ki=0.015±0.002?M and Ki`=0.014±0.003?M.?R?-CPH has Ki=0.015±0.002?M and Ki`=0.014±0.003?M.Using MCF-7 cells as a substrate for acute toxicity testing of mammalian cells,the results showed that CC₅₀?3.16 mM,and the toxicity was low.In in vivo activity experiments,acute toxicity was investigated in mice using?±?-CPH,?S?-CPH,and?R?-CPH.In vivo activity studies were conducted using a mouse gavage method and the drug was measured using a modified fistula method.The median lethal dose?LD50?was determined by tissue sectioning and imaging techniques.The results showed that?±?-CPH LD₅₀?2413 mg/kg,?S?-CPH LD₅₀?2640 mg/kg,?R?-CPH LD₅₀?2338 mg/kg.32 mg/kg of?±?-CPH,?S?-CPH,and?R?-CPH have significant effects on the inhibition of gastritis and have certain clinical significance.