Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Jing Zhang; Peng Zhan; Jingde Wu; Zhenyu Li; Yan Jiang; Weiying Ge; Christophe Pannecouque; Erik De Clercq; Xinyong Liu

doi:10.1016/j.bmc.2011.05.024

Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Bioorg Med Chem. 2011 Jul 15;19(14):4366-76. doi: 10.1016/j.bmc.2011.05.024. Epub 2011 May 23.

Authors

Jing Zhang¹, Peng Zhan, Jingde Wu, Zhenyu Li, Yan Jiang, Weiying Ge, Christophe Pannecouque, Erik De Clercq, Xinyong Liu

Affiliation

¹ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, PR China.

PMID: 21683601
DOI: 10.1016/j.bmc.2011.05.024

Abstract

A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1,6c6, and 6b1 (EC(50)=0.24 ± 0.05, 0.38 ± 0.13, 0.39 ± 0.05 μM, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50)=0.21 μM) and delavirdine (DLV) (EC(50)=0.32 μM). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Cell Line, Tumor
Crystallography, X-Ray
Dose-Response Relationship, Drug
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-2 / drug effects
Humans
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Stereoisomerism
Structure-Activity Relationship
Virus Replication / drug effects

Substances

Anti-HIV Agents
Pyrimidinones
Reverse Transcriptase Inhibitors
HIV Reverse Transcriptase