新型吡啶酮类HIV-1双靶点(RT/IN)抑制剂的设计、合成及生物活性评估

doi:10.5246/jcps.2017.01.003

中国药学(英文版) ›› 2017, Vol. 26 ›› Issue (1): 31-44.DOI: 10.5246/jcps.2017.01.003

新型吡啶酮类HIV-1双靶点(RT/IN)抑制剂的设计、合成及生物活性评估

杨全志, 盛涛, 樊宁宁, 郝亚萌, 曹源源, 郭莹, 张志丽, 田超, 刘俊义^*, 王孝伟^*

北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2016-11-05 修回日期:2016-12-15 出版日期:2017-01-22 发布日期:2016-12-20
通讯作者: Tel.: +86-010-82805203, E-mail: xiaoweiwang@bjmu.edu.cn, jyliu@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 21172014, 812111023 and 81172733) and grants from the Ministry of Science and Technology of China (Grant No. 2009ZX09301-010).

Design, synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual (RT/IN) inhibitors

Quanzhi Yang, Tao Sheng, Ningning Fan, Yameng Hao, Yuanyuan Cao, Ying Guo, Zhili Zhang, Chao Tian, Junyi Liu^*, Xiaowei Wang^*

Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2016-11-05 Revised:2016-12-15 Online:2017-01-22 Published:2016-12-20
Contact: Tel.: +86-010-82805203, E-mail: xiaoweiwang@bjmu.edu.cn, jyliu@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 21172014, 812111023 and 81172733) and grants from the Ministry of Science and Technology of China (Grant No. 2009ZX09301-010).

摘要/Abstract

摘要：

本文以吡啶酮类逆转录酶抑制剂和二酮酸类(DKA)整合酶抑制剂为先导化合物，选取必要的药效团进行高度整合并对其进行合理优化，设计出的三个系列的HIV-1 RT/IN双靶点抑制剂。采用表面等离子共振(SPR)技术及酶联免疫吸附法对目标化合物分别进行了体外抗HIV-1 RT和IN的生物活性测定。实验结果表明，化合物A2对逆转录酶和整合酶都表现出较好的抑制活性，为深入研究该类化合物作为HIV-1双靶点抑制剂提供了相关信息。

关键词: 吡啶酮衍生物, HIV-1双靶点抑制剂, 逆转录酶, 整合酶

Abstract:

Three series of novel anti-immunodeficiency virus 1 (HIV-1) dual (RT/IN) inhibitors were rationally designed by introducing a functioning diketo acid (DKA) into pyridin-2-one scaffold. To efficiently analyze inhibitory activity, these compounds were screened against HIV-1 RT and IN respectively via surface plasmon resonance (SPR), and active compounds were subsequently evaluated by enzyme assay. It was noteworthy that compound A2 exhibited moderate activity against both HIV-1 RT and IN. This result provided information for further development of pyridinone analogues as potent dual HIV-1 inhibitors.

Key words: Pyridinone derivatives, HIV-1 dual inhibitor, Reverse transcriptase, Integrase

中图分类号:

R916

Supporting:

Supporting Information

HPLC analysis of key compounds was performed on an Agilent 1260 infinity HPLC system. A 4.6 mm × 150 mm Agilent Extend-C18 column (3.5 µm partical size) and the UV absorbance detector were used with a flow rate of 1.0 mL/min.

HPLC analytical data for key compounds

Compound	Solvent system	t_R (min)	Purity (%)
A1	MeOH:H₂O=75:25	5.744	98.9
A2	MeOH:H₂O=75:25	4.773	99.6
A4	MeOH:H₂O=80:20	8.993	100
B1	MeOH:H₂O=65:35	4.690	98.9
B2	MeOH:H₂O=60:40	5.920	100
B4	MeOH:H₂O=70:30	7.005	98.3
C1	MeOH:H₂O=65:35	5.364	100
C2	MeOH:H₂O=62:38	6.031	100
C4	MeOH:H₂O=65:35	6.131	99.8

杨全志, 盛涛, 樊宁宁, 郝亚萌, 曹源源, 郭莹, 张志丽, 田超, 刘俊义, 王孝伟. 新型吡啶酮类HIV-1双靶点(RT/IN)抑制剂的设计、合成及生物活性评估[J]. 中国药学(英文版), 2017, 26(1): 31-44.

Quanzhi Yang, Tao Sheng, Ningning Fan, Yameng Hao, Yuanyuan Cao, Ying Guo, Zhili Zhang, Chao Tian, Junyi Liu, Xiaowei Wang. Design, synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual (RT/IN) inhibitors[J]. Journal of Chinese Pharmaceutical Sciences, 2017, 26(1): 31-44.

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新型吡啶酮类HIV-1双靶点(RT/IN)抑制剂的设计、合成及生物活性评估

Design, synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual (RT/IN) inhibitors

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