Synthesis and biological evaluation of pyridinone analogues as novel potent HIV-1 NNRTIs

Bioorg Med Chem. 2015 Jan 1;23(1):149-59. doi: 10.1016/j.bmc.2014.11.012.

Yuanyuan Cao ¹, Yu Zhang ², Shaotong Wu ², Quanzhi Yang ², Xuefeng Sun ², Jianxiong Zhao ², Fen Pei ², Ying Guo ², Chao Tian ², Zhili Zhang ², Haining Wang ³, Liying Ma ³, Junyi Liu ⁴, Xiaowei Wang ⁵

Affiliations

1 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Taihe Hospital Affiliated with Hubei University of Medicine, Shiyan 442000, Hubei, China.
2 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
3 State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Chinese Center for Disease Control and Prevention, Beijing 102206, China.
4 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
5 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: xiaoweiwang@bjmu.edu.cn.

PMID: 25468035 DOI: 10.1016/j.bmc.2014.11.012

Abstract

A novel 2-pyridinone scaffold was rationally designed and synthesized based on the active anti-HIV agent 1 (LAM-trans) via an efficient method. The biological results revealed that some target compounds inhibited HIV-1 Reverse Transcriptase in the lower micromolar concentration range (IC50 0.089-0.68 μm). Notably, the most promising compound 25b exhibited extremely potent inhibitory activity against HIV-1 replication with an EC50 value of 0.0563 μM and the viral selectivity index amounted to 3466.8. Molecular modeling studies were performed, and some SARs were rationalized.

Keywords

HIV-1; NNRTIs; Pyridinone analogues.

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