CONICET | Buscador de Institutos y Recursos Humanos

A considerable number of thiosemicarbazone (TSC) derivatives has been reported as antibacterial, antiviral and antiproliferative compounds. In particular, certain TSCs showed a selective inhibition of herpes simplex virus and human immunodeficiency virus infections. In this study, we report the inhibitory activity against Junin virus (JUNV), an RNA virus member of the family Arenaviridae and agent of Argentine hemorrhagic fever (AHF), of several TSCs, synthesized from aromatic ketones and terpenones, and the corresponding thiadiazoline (TDZ) derivatives, obtained by heterocyclization. The toxicity for Vero cells of 25 compounds, including TSCs, TDZs, unprotected TDZs and intermediate products, was first investigated by MTT method. According to compound solubility, the highest concentration assayed was 200 µM and the values of CC50 varied in the range 36.1 - >200 µM. Antiviral activity was evaluated by a virus yield inhibition assay in Vero cells. Only three TSC derivatives were totally inactive against JUNV and most of the remaining TSCs inhibited JUNV replication with EC50 values in the range 3.4-100 µM. The most active inhibitors showed similar or higher efficacy in vitro than ribavirin, the only drug known to be of any benefit in the treatment of patients with arenavirus infection. By contrast most of the ten TDZs assayed were not active against JUNV. No conclusive structure-activity relationships could be established but systematically higher activity was associated to TSCs synthesized from aromatic ketones. The active compound 4a, TSC of tetralone, was chosen for further characterization of the mode of action of this kind of compounds. No direct virucidal effect on JUNV virions was shown by 4a. Time course experiments indicated that the inhibitory action was exerted on a late step of JUNV replicative cycle. In addition, no alterations in viral protein synthesis in 4a-treated cells were observed suggesting that the final stage of virion maturation is the target of the compound in JUNV infected cells.

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