2-[5-取代苯并咪(噻)唑-2-硫基]-1-(4-取代苯基)乙酮缩氨基胍的合成及NHE1抑制活性

Synthesis and inhibitory effects on NHE1 of [2-(5-substituted benzimidazol(or benzothiazol)-2-ylthio)-1-(4-substituted phenylethylidene)] aminoguanidines

目的设计合成缩氨基胍类化合物并研究其NHE1抑制活性。方法以4-取代苯乙酮(1)为原料,经溴代得α-溴代物(2),再与2-巯基-5-取代苯并咪(噻)唑(3)反应得到2-(5-取代苯并咪(噻)唑-2-硫基)-1-(4-取代苯基)乙酮(4),最后与氨基胍缩合得到目标化合物;以血小板肿胀模型进行初步的体外NHE1抑制活性筛选。结果与结论合成了12个新化合物,其结构经IR、1H-NMR及MS确证。初步的药理试验表明,12个目标化合物均有一定的NHE1抑制活性,其中化合物5b和5h的活性明显优于阳性对照药卡立泊来德。

Aim In order to get some novel compounds with potent NHE1 inhibitory activity for the prevention and treatment of myocardial injury during ischemia and reperfusion, 12 target compounds of [ 2-（5-substituted benzimidazol（or benzothiazol）-2-ylthio）-1- （4-substituted phenylethylidene） ] aminoguanidines （5a - 51） were synthesized. Methods Firstly, treatment of 4-substituted phenylethanone （1） with bromine gave alpha-bromophenylethanone intermediates （2）. Secondly, substitution of the bromo group of 2 by 2-mercapto-5-substitutedbenzimidazole （or benzothiazole）.（3 ） afforded 2- （ 5-substitutedbenzimidazole （or benzothiazole）-2-ylthio）-l- （4-substitutedphenyl）ethanone （4）. Finally, condensation of 3 with aminoguanidine furnished the target compounds 5a - 51. Results and conclusion The structures of the compounds were confirmed by IR, MS, and 1H-NMR, The results of preliminary pharmacological test showed that all of compounds possess diverse NHE1 inhibitory activity, among which compounds 5b and 5h were more potent than cariporide in NHE1 inhibiton.