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目的设计合成1,3,5-三取代吡唑类化合物,并研究其对ALK5所介导的TGFβ信号通路的抑制活性,以期发现新型ALK5抑制剂。方法先以取代的苯甲醛和4-乙酰苯甲腈为原料,合成取代的查儿酮,再与芳基肼或芳基肼盐酸盐反应生成1,3,5-三取代吡唑啉,然后氧化脱氢得到相应的1,3,5-三取代吡唑类化合物,最后对官能团做适当的变换,得到目标化合物;应用基于细胞的TGF-Smad2检测评价了化合物的ALK5抑制活性。结果与结论合成29个未见报道的新目标化合物,其结构均经核磁共振谱与质谱确证,其中化合物6c显示有较好的ALK5抑制活性。
OBJECTIVE To design and synthesize 1,3,5-trisubstituted pyrazoles and study their inhibitory activity on TGFβ signaling mediated by ALK5 in order to find novel ALK5 inhibitors. Methods The substituted benzaldehyde and 4-acetyl-benzonitrile are used as the raw materials to synthesize substituted chalcones and react with arylhydrazine or arylhydrazine hydrochloride to form 1,3,5-trisubstituted pyrazolines. Then oxidatively dehydrogenated to give the corresponding 1,3,5-trisubstituted pyrazoles, and finally functional groups were transformed to obtain the target compounds. The cell-based TGF-Smad2 assay was used to evaluate the ALK5 inhibitory activity of the compounds. RESULTS AND CONCLUSIONS A total of 29 new target compounds were synthesized and their structures were confirmed by 1H NMR and MS. Compound 6c showed good ALK5 inhibitory activity.