硝基呋喃亚甲基哌啶类化合物的合成与抗结核活性

Synthesis and Antitubercular Activity of Nitrofuran-Methylene Piperidine Compounds

结核是由结核分枝杆菌引起的一种慢性呼吸道传染病,对人类的健康构成严重威胁。本文利用药效团拼接原理,将片段硝基呋喃和苯基噻唑组合,得到了19个2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)噻唑(5)和2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)-4-苯噻唑(6)系列化合物,测试了所有化合物在1和0.1μmol/L浓度下对结核分枝杆菌H37Ra的抑制率。构效关系分析表明,苯环上有取代基有利于活性,且苯环上对位取代普遍优于间位和邻位取代,对位吸电子基团取代活性优于对位供电子基团取代活性。在苯环对位吸电子基团取代中,—CF3取代的化合物2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)-(4-(4-三氟甲基)苯基)噻唑(6f)活性最高,在1和0.1μmol/L浓度下,抑制率分别为99.6%和93.4%。鉴于新化合物具有抗结核高活性,化合物6f可作为抗结核候选化合物进一步研究。

Tuberculosis is a chronic respiratory infectious disease caused by Mycobacterium tuberculosis and a serious threat to the health of people around the world.In the previous work,we adopted the strategy of combinatorial chemistry,combining the group nitrofuran and phenyl-thiazole,to generate a series of new compounds with high antitubercular activity.In this work,a methylene-piperidine group was introduced and used to replace the original amide bridge moiety to produce new derivatives 2-(1-((5-nitrofuran-2-yl)methyl)piperidin-4-yl)thiazole(5)and 2-(1-((5-nitrofuran-2-yl)methyl)piperidin-4-yl)-4-phenylthiazole(6).In total,19 compounds were synthesized and then the inhibition rate against Mycobacterium tuberculosis H37Ra was tested at the concentration of 1μmol/L and 0.1μmol/L.Based on the structure-activity relationship analysis,we found that the substitution on the benzene ring is beneficial to the activity improvement,furthermore,the para substitution is better than the meta and ortho substitution,and the electron-withdrawing group in the para position is better than the electron-donating group.In the para substitution of electron-withdrawing groups,—CF 3 substituted compound 2-(1-((5-nitrofuran-2-yl)methyl)piperidin-4-yl)-4-(4-(trifluoromethyl)phenyl)thiazole(6f)had the highest antitubercular activity,and the inhibition rates reached 99.6%and 93.4%at the concentration of 1μmol/L and 0.1μmol/L,respectively.Due to the high antitubercular activity of compound 6f,it can be further developed as an antitubercular candidate compound.