Design, synthesis and biological evaluation of novel piperazine derivatives as CCR5 antagonists

Tao Liu; Zhiyong Weng; Xiaowu Dong; Linjie Chen; Ling Ma; Shan Cen; Naiming Zhou; Yongzhou Hu

doi:10.1371/journal.pone.0053636

Design, synthesis and biological evaluation of novel piperazine derivatives as CCR5 antagonists

PLoS One. 2013;8(1):e53636. doi: 10.1371/journal.pone.0053636. Epub 2013 Jan 7.

Authors

Tao Liu¹, Zhiyong Weng, Xiaowu Dong, Linjie Chen, Ling Ma, Shan Cen, Naiming Zhou, Yongzhou Hu

Affiliation

¹ Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Lt601@zju.edu.cn

Abstract

By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC(50) values in low micromolar level. Among evaluated compounds, 23 h was found to be a CCR5 antagonist with an IC(50) value of 6.29 µM and an anti-HIV-1 inhibitor with an IC(50) value of 0.44 µM.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / pharmacology*
Biological Assay
CCR5 Receptor Antagonists*
CD4 Antigens / genetics
CD4 Antigens / metabolism
Cell Fusion
Cell Survival / drug effects
Drug Design
Gene Expression
Genes, Reporter
HEK293 Cells
HIV Envelope Protein gp120 / genetics
HIV Envelope Protein gp120 / metabolism
HIV-1 / drug effects*
HIV-1 / growth & development
Humans
Inhibitory Concentration 50
Luciferases
Piperazines / chemical synthesis*
Piperazines / pharmacology*
Receptors, CCR5 / metabolism
Structure-Activity Relationship

Substances

Anti-HIV Agents
CCR5 Receptor Antagonists
CD4 Antigens
HIV Envelope Protein gp120
Piperazines
Receptors, CCR5
gp120 protein, Human immunodeficiency virus 1
Luciferases

Grants and funding

This study was supported by grants from the National Nature Science Foundation of China (number 81072515). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.