1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus

Alexander N Geisman; Vladimir T Valuev-Elliston; Alexander A Ozerov; Anastasia L Khandazhinskaya; Alexander O Chizhov; Sergey N Kochetkov; Christophe Pannecouque; Lieve Naesens; Katherine L Seley-Radtke; Mikhail S Novikov

doi:10.1016/j.bmc.2016.04.010

1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus

Bioorg Med Chem. 2016 Jun 1;24(11):2476-2485. doi: 10.1016/j.bmc.2016.04.010. Epub 2016 Apr 5.

Affiliations

¹ Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq., 1, Volgograd 400131, Russia.
² Engelhardt Institute of Molecular Biology, Russian Academy of Science, Vavilov Str., 32, Moscow 119991, Russia.
³ Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky pr., 47, Moscow 119991, Russia.
⁴ KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
⁵ Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: [email protected].

PMID: 27112451
DOI: 10.1016/j.bmc.2016.04.010

Abstract

A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation.

Keywords: HIV; Influenza virus; NNRTIs; Non-nucleoside reverse transcriptase inhibitors; Uracil.

Publication types

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

MeSH terms

Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cells, Cultured
Dogs
Dose-Response Relationship, Drug
HIV-1 / drug effects*
Influenza A Virus, H1N1 Subtype / drug effects*
Madin Darby Canine Kidney Cells / drug effects
Madin Darby Canine Kidney Cells / virology
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Uracil / analogs & derivatives*
Uracil / chemical synthesis
Uracil / chemistry
Uracil / pharmacology*

Substances

Antiviral Agents
Uracil