硝基呋喃亚甲基哌啶类化合物的合成与抗结核活性

doi:10.11944/j.issn.1000-0518.2020.02.190206

摘要/Abstract

摘要：

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0.1 μmol/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0.1 μmol/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。

关键词: 硝基呋喃, 亚甲基哌啶, 结核分枝杆菌, 构效关系

Abstract:

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 1 μmol/L and 0.1 μmol/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, —CF₃ 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 1 μmol/L and 0.1 μmol/L, respectively. Due to the high antitubercular activity of compound 6f, it can be further developed as an antitubercular candidate compound.

Key words: nitrofuran, methylene piperidine, Mycobacterium tuberculosis, structure-activity relationship

何冰,钟鑫鑫,冉凯,奉强,余登斌,韩涛,李仲辉,余洛汀. 硝基呋喃亚甲基哌啶类化合物的合成与抗结核活性[J]. 应用化学, 2020, 37(2): 134-143.

HE Bing,ZHONG Xinxin,RAN Kai,FENG Qiang,YU Dengbin,HAN Tao,LI Zhonghui,YU Luoting. Synthesis and Antitubercular Activity of Nitrofuran-Methylene Piperidine Compounds[J]. Chinese Journal of Applied Chemistry, 2020, 37(2): 134-143.

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