Synthesis and Antitumor Evaluation of 2,4-Substituted Quinazoline Derivatives Containing Benzimidazole

doi:10.6023/cjoc201804016

Chin. J. Org. Chem. ›› 2018, Vol. 38 ›› Issue (10): 2673-2679.DOI: 10.6023/cjoc201804016 Previous Articles Next Articles

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含苯并咪唑的2,4-取代喹唑啉衍生物的合成及抗肿瘤活性评价

栗娜^a,b, 辛景超^a,b, 孟娅琪^a,b, 李二冬^a,b, 马启胜^a,b, 包崇男^a,b, 杨鹏^a,b, 宋攀攀^a,b, 崔飞^a,b, 赵培荣^b, 李雯^a,b, 可钰^a,b, 张秋荣^a,b, 刘宏民^a,b

a 郑州大学药学院郑州 450001;
b 新药创制与药物安全性评价河南省协同创新中心郑州 450001

收稿日期:2018-04-10 修回日期:2018-05-04 发布日期:2018-06-06
通讯作者: 可钰,E-mail:ky@zzu.edu.cn;张秋荣,E-mail:zqr406@sina.com;刘宏民,E-mail:liuhm@zzu.edu.cn E-mail:ky@zzu.edu.cn;zqr406@sina.com;liuhm@zzu.edu.cn
基金资助:
国家自然科学基金（No.81430085）、河南省自然科学基金（No.182300410321）和河南省科技厅（No.182102310249）资助项目.

Synthesis and Antitumor Evaluation of 2,4-Substituted Quinazoline Derivatives Containing Benzimidazole

Li Na^a,b, Xin Jingchao^a,b, Meng Yaqi^a,b, Li Erdong^a,b, Ma Qisheng^a,b, Bao Chongnan^a,b, Yang Peng^a,b, Song Panpan^a,b, Cui Fei^a,b, Zhao Peirong^b, Li Wen^a,b, Ke Yu^a,b, Zhang Qiurong^a,b, Liu Hongmin^a,b

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001;
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001

Received:2018-04-10 Revised:2018-05-04 Published:2018-06-06
Contact: 10.6023/cjoc2018004016 E-mail:ky@zzu.edu.cn;zqr406@sina.com;liuhm@zzu.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (No. 81430085), the Natural Science Foundation of Henan Province (No. 182300410321) and the Technology Department Project of Henan Province (No. 182102310249).

1. Synthesis and Antitumor Evaluation of 2,4-Substituted Quinazoline Derivatives Containing Benzimidazole.PDF(1452KB)

Abstract

In order to find more efficient and economical antitumor drugs, a series of novel 2,4-substituted quinazoline derivatives containing benzimidazole were designed, synthesized and evaluated for their antitumor activities on two human tumor cell lines including human gastric cancer cells (MGC-803), human breast cancer cells (MCF-7) and the normal human gastric epithelial cell line (GES-1) by using thiazolyl blue tetrazolium bromide (MTT) assay in vitro. Among all the tested compounds, some compounds displayed moderate to potent antitumor activities against MGC-803 and MCF-7. When the 4-position of quinazoline was substituted by different aromatic amines, 2-(((1H-benzo[d]imidazol-2-yl)methyl)thio)-N-(4-methoxyphen-yl)quinazolin-4-amine (15e) had good anti-tumor activity against MGC-803 with IC₅₀ value of 4.60 μmol·L^-1. When the 4-position of quinazoline was replaced by different chalcone, (E)-1-(4-((2-(((1H-benzo[d]imidazol-2-yl)methyl)thio)quinazo-lin-4-yl)amino)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one (15k) had a strong anti-tumor activity against MGC-803 with IC₅₀ value of 0.97 μmol·L^-1, which was significantly better than compound 15e. However, the toxicity of compound 15e was more serious than compound 15k whose toxicity was similar to that of the control drug 5-fluorouracil and gefitinib against GES-1. The result of docking with epidermal growth factor receptor (EGFR) suggested that the binding mode of 15k was better than that of 15e. It is believed that this work would be very useful for developing a new series of EGFR inhibitors.

Key words: quinazoline, benzimidazole, synthesis, antitumor activities

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Li Na, Xin Jingchao, Meng Yaqi, Li Erdong, Ma Qisheng, Bao Chongnan, Yang Peng, Song Panpan, Cui Fei, Zhao Peirong, Li Wen, Ke Yu, Zhang Qiurong, Liu Hongmin. Synthesis and Antitumor Evaluation of 2,4-Substituted Quinazoline Derivatives Containing Benzimidazole[J]. Chin. J. Org. Chem., 2018, 38(10): 2673-2679.

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含苯并咪唑的2,4-取代喹唑啉衍生物的合成及抗肿瘤活性评价

Synthesis and Antitumor Evaluation of 2,4-Substituted Quinazoline Derivatives Containing Benzimidazole

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