Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase

Yixing Sun; Weisi Xu; Ningning Fan; Xuefeng Sun; Xianling Ning; Liying Ma; Junyi Liu; Xiaowei Wang

doi:10.1016/j.bmc.2016.12.035

Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase

Bioorg Med Chem. 2017 Feb 1;25(3):1076-1084. doi: 10.1016/j.bmc.2016.12.035. Epub 2016 Dec 24.

Authors

Yixing Sun¹, Weisi Xu², Ningning Fan¹, Xuefeng Sun¹, Xianling Ning¹, Liying Ma³, Junyi Liu⁴, Xiaowei Wang⁵

Affiliations

¹ Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
² State Key Laboratory of Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center of Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Changping District, Beijing 102206, China.
³ State Key Laboratory of Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center of Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Changping District, Beijing 102206, China. Electronic address: mal@chinaaids.cn.
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. Electronic address: jyliu@bjmu.edu.cn.
⁵ Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: xiaoweiwang@bjmu.edu.cn.

PMID: 28082070
DOI: 10.1016/j.bmc.2016.12.035

Abstract

Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5.

Keywords: CCR5 receptor; HIV dual inhibitors; HIV integrase; Sulfones; Sulfoxides.

MeSH terms

Anilides / chemical synthesis
Anilides / chemistry
Anilides / pharmacology
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Cell Line
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design
HIV Integrase / metabolism*
HIV Integrase Inhibitors / chemical synthesis
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology*
HIV-1 / drug effects*
HIV-1 / enzymology
Humans
Microbial Sensitivity Tests
Molecular Structure
Receptors, CCR5 / metabolism*
Structure-Activity Relationship
Styrenes / chemical synthesis
Styrenes / chemistry
Styrenes / pharmacology
Sulfones / chemical synthesis
Sulfones / chemistry
Sulfones / pharmacology*
Sulfoxides / chemical synthesis
Sulfoxides / chemistry
Sulfoxides / pharmacology*
Virus Replication / drug effects

Substances

Anilides
Anti-HIV Agents
CCR5 protein, human
HIV Integrase Inhibitors
Receptors, CCR5
Styrenes
Sulfones
Sulfoxides
HIV Integrase
p31 integrase protein, Human immunodeficiency virus 1