Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists

Suwen Hu; Zhilong Wang; Tingjun Hou; Xiaodong Ma; Jing Li; Tao Liu; Xin Xie; Yongzhou Hu

doi:10.1016/j.bmc.2014.12.052

Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists

Bioorg Med Chem. 2015 Mar 1;23(5):1157-68. doi: 10.1016/j.bmc.2014.12.052. Epub 2014 Dec 30.

Authors

Suwen Hu¹, Zhilong Wang², Tingjun Hou³, Xiaodong Ma¹, Jing Li², Tao Liu⁴, Xin Xie⁵, Yongzhou Hu⁶

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
⁴ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: Lt601@zju.edu.cn.
⁵ State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xxie@mail.shcnc.ac.cn.
⁶ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.

PMID: 25638498
DOI: 10.1016/j.bmc.2014.12.052

Abstract

Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10μM.

Keywords: 2-Methylpiperazine derivatives; Anti-HIV-1 agent; CCR5 antagonist.

Publication types

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

MeSH terms

Animals
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology
CHO Cells
Cricetinae
Cricetulus
Drug Design
HIV-1 / drug effects
HIV-1 / pathogenicity
Humans
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology*
Receptors, CCR5 / drug effects*

Substances

2-methyl piperazine
Anti-HIV Agents
CCR5 protein, human
Piperazines
Receptors, CCR5