Design and synthesis of a novel series of non-nucleoside HIV-1 inhibitors bearing pyrimidine and N-substituted aromatic piperazine

KaiJun Jin; YaLi Sang; Erik De Clercq; Christophe Pannecouque; Ge Meng

doi:10.1016/j.bmcl.2018.10.010

Design and synthesis of a novel series of non-nucleoside HIV-1 inhibitors bearing pyrimidine and N-substituted aromatic piperazine

Bioorg Med Chem Lett. 2018 Dec 1;28(22):3491-3495. doi: 10.1016/j.bmcl.2018.10.010. Epub 2018 Oct 9.

Authors

KaiJun Jin¹, YaLi Sang¹, Erik De Clercq², Christophe Pannecouque², Ge Meng³

Affiliations

¹ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
² Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
³ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China. Electronic address: mgfudan@fudan.edu.cn.

PMID: 30318436
DOI: 10.1016/j.bmcl.2018.10.010

Abstract

A novel series of substituted piperazine-1-yl-pyrimidine derivatives were designed and synthesized as a new type of HIV-1 non-nucleoside inhibitors. Various N-substituted aromatic groups were incorporated into the piperazine ring through a simple and practical route to investigate the biological activity of these target compounds against wild-type and resistant strains of HIV-1. All of the target compounds were also evaluated as HIV-1 reverse transcriptase inhibitors in MT-4 cell cultures. The biological results showed that six of these compounds displayed inhibitory activities against the wild-type strain, among of which 7q and 7t were found to be the two most active analogues possessing EC₅₀ values of 31.50 μM and 3.36 μM, respectively. Molecular modeling studies of 7q provide valuable information for developing new anti-HIV-1 inhibitors.

Keywords: Diarylpyrimidine; HIV-1; Molecular modeling; Piperazine; Reverse transcriptase.

Publication types

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

MeSH terms

Binding Sites
Cell Line
Drug Design*
Drug Resistance, Viral / drug effects
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / genetics
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-1 / enzymology
Humans
Molecular Docking Simulation
Nitrogen / chemistry
Piperazine / chemistry*
Protein Structure, Tertiary
Pyrimidines / chemistry*
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Pyrimidines
Reverse Transcriptase Inhibitors
Piperazine
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
Nitrogen