Synthesis, Cytotoxicity and Antiviral Activity Against Vaccinia Virus of 2-(3-Coumarinyl)-1-Hydroxyimidazoles

Abstract

Background: In 1980, smallpox became the first viral disease eradicated through vaccination. After the termination of the Smallpox Eradication Program, the global immunization of the population also ceased. Now, most people do not have any immunity against infections caused by orthopoxviruses. Emerging cases of zoonotic orthopox infections transferring to humans inspire the search for new small organic molecules possessing antiviral activity against orthopoxviruses.

Objective: Here, we present the synthesis and evaluation of antiviral activity against one of the orthopoxviruses, i.e., Vaccinia virus, of hybrid structures containing 1-hydroxyimidazole and benzopyranone moieties.

Methods: Novel 2-(3-coumarinyl)-1-hydroxyimidazoles were synthesized. Their prototropic tautomerism was considered using ¹H NMR spectroscopy. Antiviral activity of both new 2-(3-coumarinyl)- 1-hydroxyimidazoles and previously described 2-(3-chromenyl)-1-hydroxyimidazoles against Vaccinia virus was evaluated in Vero cell culture.

Results: Newly synthesized 2-(3-coumarinyl)-1-hydroxyimidazoles existed in CDCl₃ as a mixture of prototropic tautomers (N-hydroxyimidazole and imidazole N-oxide), transition to DMSO-d6 resulting in the prevalence of N-oxide tautomer. Evaluation of cytotoxicity and antiviral activity against Vaccinia virus was performed in Vero cell culture. Compounds possessing high antiviral activity were present in both series. It was demonstrated that the structure of heterocyclic substituent in position 2 of imidazole impacted the cytotoxicity of substances under consideration. Thus, molecules containing coumarin moiety exhibited lower toxicity than similarly substituted 2-(3-chromenyl)-1- hydroxyimidazoles.

Conclusion: Perspective virus inhibiting compounds possessing antiviral activity against Vaccinia virus were revealed in the series of 2-(3-coumarinyl)-1-hydroxyimidazoles.

Keywords: 1-hydroxyimidazole; Vaccinia virus; antiviral activity; chromone; coumarin; cytotoxicity; orthopoxvirus; prototropic tautomerism.