Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides

Denis A Babkov; Anastasia L Khandazhinskaya; Alexander O Chizhov; Graciela Andrei; Robert Snoeck; Katherine L Seley-Radtke; Mikhail S Novikov

doi:10.1016/j.bmc.2015.09.033

Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides

Bioorg Med Chem. 2015 Nov 1;23(21):7035-44. doi: 10.1016/j.bmc.2015.09.033. Epub 2015 Sep 21.

Authors

Denis A Babkov¹, Anastasia L Khandazhinskaya², Alexander O Chizhov³, Graciela Andrei⁴, Robert Snoeck⁴, Katherine L Seley-Radtke⁵, Mikhail S Novikov¹

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, Vavilova 32, Moscow 119991, Russia.
³ Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky pr., 47, Moscow 119991, Russia.
⁴ Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
⁵ Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: kseley@umbc.edu.

Abstract

The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[ω-(4-bromophenoxy)alkyl]uracil derivatives--previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N(3) increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action.

Keywords: Antiviral; Human cytomegalovirus; Non-nucleoside inhibitor; Uracil; Varicella zoster virus.

Publication types

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

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry*
Acetamides / toxicity
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry*
Antiviral Agents / toxicity
Cell Line
Cell Proliferation / drug effects
Cytomegalovirus / physiology*
DNA Viruses / drug effects
DNA Viruses / physiology
Drug Evaluation, Preclinical
Herpesvirus 3, Human / drug effects
Herpesvirus 3, Human / physiology*
Humans
RNA Viruses / drug effects
RNA Viruses / physiology
Structure-Activity Relationship
Uracil / chemistry*
Virus Replication / drug effects

Substances

Acetamides
Antiviral Agents
Uracil
acetamide