Novel derivatives of thiohydantoin-containing tetrahydro-β-carboline possess activity against influenza virus at late stages of viral cycle without affecting viral neuraminidase

Abstract

Influenza infection represents a serious challenge for virological surveillance and healthcare systems in all countries globally. Despite obvious success in control of influenza through vaccination and antiviral drug development, this infection remains poorly controlled due to antigenic drift and fast selection of drug-resistant viral variants. The design of novel drugs with alternative targets and mechanisms of action is, therefore, an important goal for medical science worldwide. In the current study, we describe the chemical synthesis of novel tetrahydro-β-carboline derivatives containing a thiohydantoin fragment, as well as their antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). In general, the library of compounds was of low toxicity. Of the 23 compounds under investigation, 10 (43.5%) displayed a selectivity index (SI) of 10 or higher, their activity strongly exceeding that of the reference compound rimantadine. The most active compounds have also demonstrated suppressing activity against the phylogenetically distinct influenza virus of type B. These compounds, similar to the reference compound zanamivir, were active at very late stages of the viral cycle (4–6 h postinfection), suggesting interference with processes of virion assembly and budding. However, no direct inhibiting activity against viral neuraminidase has been demonstrated. The results obtained can be considered as a rationale for further structural optimization and study of this group as potential broad-range antivirals effective against influenza viruses.