ABSTRACT
Here we report on the results obtained from an antiviral screening, including herpes simplex virus, vaccinia virus, vesicular stomatitis virus, Coxsackie B4 virus or respiratory syncytial virus, parainfluenza-3 virus, reovirus-1 and Punta Toro virus, of three 2-hydroxy-3-methoxyphenyl acylhydrazone compounds in three cell lines (i.e. human embryonic lung fibroblast cells, human cervix carcinoma cells, and African Green monkey kidney cells). Interesting antiviral EC50 values are obtained against herpes simplex virus-1 and vaccinia virus. The biological activity of acylhydrazones is often attributed to their metal coordinating abilities, so potentiometric and microcalorimetric studies are here discussed to unravel the behavior of the three 2-hydroxy-3-methoxyphenyl compounds in solution. It is worth of note that the acylhydrazone with the higher affinity for Cu(II) ions shows the best antiviral activity against herpes simplex and vaccinia virus (EC50 ~ 1.5 µM, minimal cytotoxic concentration = 60 µM, selectivity index = 40).
Subject(s)
Antiviral Agents/pharmacology , Chelating Agents/pharmacology , Hydrazones/pharmacology , Simplexvirus/drug effects , Vaccinia virus/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Cell Line , Cell Line, Tumor , Chelating Agents/chemical synthesis , Chelating Agents/metabolism , Chlorocebus aethiops , Copper/metabolism , Epithelial Cells/drug effects , Epithelial Cells/virology , Fibroblasts/drug effects , Fibroblasts/virology , Humans , Hydrazones/chemical synthesis , Hydrazones/metabolism , Inhibitory Concentration 50 , Magnesium/metabolism , Manganese/metabolism , Orthoreovirus, Mammalian/drug effects , Orthoreovirus, Mammalian/growth & development , Orthoreovirus, Mammalian/metabolism , Parainfluenza Virus 3, Human/drug effects , Parainfluenza Virus 3, Human/growth & development , Parainfluenza Virus 3, Human/metabolism , Phlebovirus/drug effects , Phlebovirus/growth & development , Phlebovirus/metabolism , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/growth & development , Respiratory Syncytial Viruses/metabolism , Simplexvirus/growth & development , Simplexvirus/metabolism , Vaccinia virus/growth & development , Vaccinia virus/metabolism , Vero Cells , Vesiculovirus/drug effects , Vesiculovirus/growth & development , Vesiculovirus/metabolismABSTRACT
Acylhydrazones are very versatile ligands and their coordination properties can be easily tuned, giving rise to metal complexes with different nuclearities. In the last few years, we have been looking for new pharmacophores able to coordinate simultaneously two metal ions, because many enzymes have two metal ions in the active site and their coordination can be a successful strategy to inhibit the activity of the metalloenzyme. As a part of this ongoing research, we synthesized the acylhydrazone H2L and its complexes with Mg(II), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). Their characterization, both in solution--also by means of potentiometric studies--and in the solid state, evidenced the ability of the o-vanillin hydrazone scaffold to give rise to different types of metal complexes, depending on the metal and the reaction conditions. Furthermore, we evaluated both the free ligand and its metal complexes in in vitro studies against a panel of diverse DNA- and RNA-viruses. In particular, the Mg(II), Mn(II), Ni(II) and Zn(II) complexes had EC50 values in the low micromolar range, with a pronounced activity against vaccinia virus.
