Design,Synthesis And Biololgical Evaluation Of N-(Benzofuran-5yl) Isonicotinamiden Derivative

Objective:Xanthine oxidoreductase?XOR?is a key enzyme involved in the occurrence and development of gout and an important target for the development of anti-gout drugs.Studies have shown that xanthine oxidase is closely related to the occurrence of gout.By inhibiting xanthine oxidase,it can effectively reduce plasma uric acid level and can be used to prevent and treat gout and hyperuricemia.So far,clinically approved xanthine oxidase inhibitors have many serious adverse reactions,such as interstitial nephritis,renal failure,liver toxicity,vasculitis,rashes of varying severity,and life-threatening hypersensitivity reactions.Syndrome?hypersensitivity syndrome?,etc.Topirastat currently developed in Japan has better curative effect and lower side effects.In combination with the preparation and activity research of topirastat,it's necessary to develop a newer xanthine oxidase inhibitor to obtain better results.Research methods:This paper starts with the research on the synthesis of topirastat and the molecular simulation of drug targets,and summarizes the structure-activity relationship of existing XO inhibitors.His synthetic route,and designed and synthesized a new type of XO inhibitors-benzofuran ring-derived compounds.A new structure type XO inhibitor was used for synthesis research:p-nitrophenol was used as a raw material to react with paraformaldehyde under the catalysis of tetrabutylammonium bromide to obtain 2-chloromethylphenol?2?.Phenylphosphine is subjected to substitution reaction to obtain 2-chloromethylphenol.Triphenylphosphine salt?3?.In the presence of pyridine and triethylamine,the acid chloride was added to carry out the cyclization reaction to obtain 2-alkyl-5-nitrobenzofuran?4?,and then reacted with hydrogen to obtain 2-alkane under the catalysis of palladium on carbon.5-Aminobenzofuran?5?.Finally,a condensation reaction with 2-substituted isonicotinic acid is carried out to form N-?2-alkylbenzofuran-5yl?-2`-substituted isonicotinamide?6?to obtain the target compound?WYH1-01?16?.Using WYH1-05?08 and WYH1-13?16 as raw materials,N-?3-nitro-2-alkylbenzofuran-5yl?-2-substituted isonicotinamide?12?is obtained after nitration,and then The target product?WYH 2-01?08?was obtained.Using WYH1-05?08 and WYH1-13?16 as raw materials,N-?3-formyl-2-alkylbenzofuran-5yl?-2-substituted isonicotinamide?13?is obtained after formylation,and then The target product was obtained?WYH 3-01?08?.In vitro activity studies were performed on the synthesized target compounds:Because uric acid has a maximum absorption peak at 294nm,by measuring the change in absorbance at 294 nm between the administration group and the blank group,the inhibitory activity of the sample on XO can be quickly determined Calculate the IC₅₀0 value.The structures of all target compounds were confirmed by MS,¹H NMR and ¹³C NMR.Results and discussion:?1?32 target compounds were designed and synthesized,all of which have not been reported.?2?Among the target compounds,the compounds with better activity are(IC₅₀=4.1?M),(IC₅₀=3.0?M),and the inhibition rate is>60%.