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

Yuanyuan Cao; Yu Zhang; Shaotong Wu; Quanzhi Yang; Xuefeng Sun; Jianxiong Zhao; Fen Pei; Ying Guo; Chao Tian; Zhili Zhang; Haining Wang; Liying Ma; Junyi Liu; Xiaowei Wang

doi:10.1016/j.bmc.2014.11.012

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. Epub 2014 Nov 14.

Authors

Yuanyuan Cao¹, Yu Zhang², Shaotong Wu², Quanzhi Yang², Xuefeng Sun², Jianxiong Zhao², Fen Pei², Ying Guo², Chao Tian², Zhili Zhang², Haining Wang³, Liying Ma³, Junyi Liu⁴, Xiaowei Wang⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / chemistry
HIV-1 / enzymology*
Humans
Models, Molecular
Molecular Docking Simulation
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship

Substances

Pyridones
HIV Reverse Transcriptase