Fluorescent octahydrophenazines as novel inhibitors against herpes simplex viruses

Eur J Med Chem. 2024 Sep 5:275:116580. doi: 10.1016/j.ejmech.2024.116580. Epub 2024 Jun 11.

Abstract

A new series of racemic fluorescent octahydrophenazines (rac-PZ1-11) have been designed and synthesized via the efficient nucleophilic aromatic substitution (SNAr) of tetrafluorobenzenedinitriles (1a-c) and racemic cyclohexane-1,2-diamines (rac-2a and b). The bioactivities of these racemic rac-PZs (20 μM) against herpes simplex virus type-1 (HSV-1) were evaluated by the relative cell viability of Vero cells infected with HSV-1. It was found that rac-PZ3 shows much higher anti-HSV-1 activity than others, with EC50 = 9.2 ± 1.4 μM. Further investigation into the anti-HSV activities of rac-PZ3 and its enantiomers RR- and SS-PZ3 indicates that rac-PZ3 can also efficiently inhibit HSV-2 and even ACV-resistant HSV-2 (EC50 = 11.0 ± 2.3 and 14.9 ± 2.8 μM, respectively), SS-PZ3 has better activities against HSV-1, HSV-2 and ACV-resistant HSV-2 (EC50 = 4.1 ± 1.1, 5.8 ± 1.0 and 7.9 ± 1.2 μM, respectively), but RR-PZ3 has almost no antiviral activities. The primary mechanism study indicates that rac-PZ3 efficiently reverses the HSV-1/2-induced cytopathic effect and suppresses the expression of viral mRNA and proteins. In addition, rac-, RR- and SS-PZ3 possess excellent fluorescence properties with almost the same emission wavelength and high fluorescence quantum yields (ΦF = 90.3-92.3 % in cyclohexane solutions and 54.4-57.3 % in solids) and can target endoplasmic reticulum and cell membrane. The efficient anti-HSV bioactivities and excellent fluorescence of PZ3 prove its potential applications in antiviral therapy and biological imaging.

Keywords: Herpesvirus inhibitor; Nucleophilic aromatic substitution; Octahydrophenazine; Structure-activity relationship.

MeSH terms

  • Animals
  • Antiviral Agents* / chemical synthesis
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology
  • Herpesvirus 1, Human* / drug effects
  • Herpesvirus 2, Human* / drug effects
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Structure-Activity Relationship
  • Vero Cells

Substances

  • Antiviral Agents
  • Fluorescent Dyes
  • Piperazines