Synthesis And Aldose Reductase Inhibitory Activity Of 1-acetyl-5-(4-fluoro Phenyl)-1H-pyrrole-3-base Acetate

At present,the study of aldose reductase inhibitors?ARIs?is considered as an i mportant direction to treat diabetic complications effectively.We summarized and st udied the three kinds of main structure of aldose reductase inhibitors and structure-activity relationship,and in accordance with the theoretical model,a new type of al dose reductase inhibitor 1-acetyl-5-phenyl-?4-fluoride?-1H-pyrrole-3-yl acetate?4-F-AP PA?was synthesized,4-fluoride cinnamic acid as raw material,through oxidation of potassium bisulfate,open the cycloaddition reaction of acetic anhydride catalyst,th e total yield was 51%,the purity is more than 98%.its structure was confirmed by IR,¹H NMR,¹³C NMR and ESI-MS.The aldose reductase was extracted to verify th e enzyme activity,and an aldose reductase inhibitor activity assay system was estab lished.The inhibitory activity of aldose reductase of the compound was studied and measured the IC₅₀ value of 7.2×10^-2?M,better than epalrestat.The research work of this thesis is mainly divided into three parts.The first part reviewed the importance of aldose reductase in diabetic complications.Based on the structural features of aldose reductase,new targets were identified.At the same time,the aldose reductase was identified as the main cause of diabetic complications due to the abnormality of the polyol pathway.The current research status of anti-diabetic complication drugs,the types of aldose reductase inhibitor drugs and their important role in the treatment of diabetic complications are highlighted.Finally,the development ideas of the paper are summarized.The second part is mainly the synthetic experiment part.Firstly,the target compounds were screened out through the theoretical model and the synthesis routes of several target compounds were designed.Compound 1 was synthesized through the oxidation of potassium bisulfate using commercially available 4-fluorocinnamic acid as a starting material.Compound 2 is synthesized by ring opening reaction of epoxides under compound1.4-F-APPA is a synthesis of compound 2 catalyzed by acetic anhydride and a series of reactions and processes.At the same time,we optimized the synthesis route and synthesis conditions for each step so that the yield and product purity of each step reached a more desirable level,and the pattern characterization and structure of each step compound were confirmed.The third part is mainly the activity experiment.We used fresh bovine eye lens as the donor to extract,purify and identify aldose reductase,determine pure enzyme activity,and then establish an ARIs activity assay system.The ARIs activity of the three target compounds was measured under the same conditions,and the activity of the three compounds was measured,and the aldose reductase inhibitory activities were:4-F-APPA>compound 1>compound 2.We selected the 4-F-APPA with the highest activity,and determined the IC₅₀ value of 4-F-APPA and positive control EPST under the same condition.After comparison,the inhibitory activity of aldose reductase in 4-F-APPA was better than that of EPST.In summary,we designed and synthesized 1-acetyl-5-phenyl-?4-fluoride?-1H-pyr role-3-yl acetate?4-F-APPA?as a novel aldose reductase inhibitors.The synthesis pro cess is easy to realize,the product yield and purity are high,and its activity is hig her than that of commercially available EPST.This study provides a new drug can didate molecule for the study of anti-diabetic complication drugs.