Phenotypic Test of Benzo[4,5]imidazo[1,2-c]pyrimidinone-Based Nucleoside and Non-Nucleoside Derivatives against DNA and RNA Viruses, Including Coronaviruses
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Published:2023-09-26
Issue:19
Volume:24
Page:14540
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Kamzeeva Polina1, Petushkov Ivan23, Knizhnik Ekaterina45, Snoeck Robert6, Khodarovich Yuri1, Ryabukhina Ekaterina1, Alferova Vera1ORCID, Eshtukov-Shcheglov Artur1, Belyaev Evgeny7, Svetlova Julia4, Vedekhina Tatiana4ORCID, Kulbachinskiy Andrey23, Varizhuk Anna45, Andrei Graciela6ORCID, Aralov Andrey1ORCID
Affiliation:
1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia 2. Institute of Molecular Genetics, National Research Centre ‘Kurchatov Institute’, 123182 Moscow, Russia 3. Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia 4. Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia 5. Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia 6. Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium 7. Frumkin Institute of Physical Chemistry and Electrochemistry, RAS, 119071 Moscow, Russia
Abstract
Emerging and re-emerging viruses periodically cause outbreaks and epidemics around the world, which ultimately lead to global events such as the COVID-19 pandemic. Thus, the urgent need for new antiviral drugs is obvious. Over more than a century of antiviral development, nucleoside analogs have proven to be promising agents against diversified DNA and RNA viruses. Here, we present the synthesis and evaluation of the antiviral activity of nucleoside analogs and their deglycosylated derivatives based on a hydroxybenzo[4,5]imidazo[1,2-c]pyrimidin-1(2H)-one scaffold. The antiviral activity was evaluated against a panel of structurally and phylogenetically diverse RNA and DNA viruses. The leader compound showed micromolar activity against representatives of the family Coronaviridae, including SARS-CoV-2, as well as against respiratory syncytial virus in a submicromolar range without noticeable toxicity for the host cells. Surprisingly, methylation of the aromatic hydroxyl group of the leader compound resulted in micromolar activity against the varicella-zoster virus without any significant impact on cell viability. The leader compound was shown to be a weak inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase. It also inhibited biocondensate formation important for SARS-CoV-2 replication. The active compounds may be considered as a good starting point for further structure optimization and mechanistic and preclinical studies.
Funder
Russian Science Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference43 articles.
1. Chowell, G., Echevarría-Zuno, S., Viboud, C., Simonsen, L., Tamerius, J., Miller, M.A., and Borja-Aburto, V.H. (2011). Characterizing the Epidemiology of the 2009 Influenza A/H1N1 Pandemic in Mexico. PLoS Med., 8. 2. Cenciarelli, O., Pietropaoli, S., Malizia, A., Carestia, M., D’Amico, F., Sassolini, A., Di Giovanni, D., Rea, S., Gabbarini, V., and Tamburrini, A. (2015). Ebola Virus Disease 2013-2014 Outbreak in West Africa: An Analysis of the Epidemic Spread and Response. Int. J. Microbiol., 2015. 3. MERS Coronavirus: Diagnostics, Epidemiology and Transmission;Mackay;Virol. J.,2015 4. Viral Subversion of the Host Protein Synthesis Machinery;Walsh;Nat. Rev. Microbiol.,2011 5. Drug Repurposing for Viral Infectious Diseases: How Far Are We?;Mercorelli;Trends Microbiol.,2018
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