Host Dihydrofolate Reductase (DHFR)-directed Cycloguanil Analogues Endowed With Activity Against Influenza Virus and Respiratory Syncytial Virus

Eur J Med Chem. 2017 Jul 28;135:467-478. doi: 10.1016/j.ejmech.2017.04.070. Epub 2017 Apr 27.

Abstract

We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC50 = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC50 ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC50 = 5.8 μM, SI > 43).

Keywords: 1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-RSV activity; Anti-influenza A and B viruses activity; Host (human) DHFR inhibition.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Folic Acid Antagonists / chemical synthesis
  • Folic Acid Antagonists / chemistry
  • Folic Acid Antagonists / pharmacology*
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects*
  • Influenza B virus / drug effects*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Proguanil / chemical synthesis
  • Proguanil / chemistry
  • Proguanil / pharmacology*
  • Respiratory Syncytial Viruses / drug effects*
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / metabolism*
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • Antiviral Agents
  • Folic Acid Antagonists
  • Triazines
  • cycloguanil
  • Tetrahydrofolate Dehydrogenase
  • Proguanil