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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*   

  1. 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:

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: 

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
tR (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