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

doi:10.5246/jcps.2017.01.003

Journal of Chinese Pharmaceutical Sciences ›› 2017, Vol. 26 ›› Issue (1): 31-44.DOI: 10.5246/jcps.2017.01.003

• Original articles • Previous Articles Next Articles

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).

Abstract

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

CLC Number:

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

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

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