Inhibitory effect of thiosemicarbazone derivatives on Junin virus multiplication in vitro

GARCÍA C.; B. BROUSSE; M. CARLUCCI; A. MOGLIONI; M. MARTINS ALHO; G. MOLTRASIO; N. D´ACCORSO; E. B. DAMONTE

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY

Año: 2003 vol. 14 p. 99 - 105

0956-3202

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; mso-layout-grid-align:none; punctuation-wrap:simple; text-autospace:none; font-size:10.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:ES-TRAD;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> The inhibitory effect of several thiosemicarbazones (TSCs), synthesized from aromatic ketones and terpenones, and their heterocyclic thiadiazoline (TDZ) derivatives, was investigated against Junin virus (JUNV), an arenavirus agent of Argentine hemorrhagic fever. From the 25 compounds tested, six compounds belonging to the TSC group were found to be selective inhibitors of JUNV, with EC50 (effective concentration 50 %) values determined by a virus yield inhibition assay in the range 3.4 – 12.5 µM, and selectivity indices greater than 10. By contrast, most of the TDZs obtained by heterocyclization of the TSCs were not active against JUNV. No conclusive structure-activity relationships could be established but systematically higher activity was associated to TSCs derived from aromatic ketones. The mode of action of one of the most active compound, the 3,4-dihydronaphtalen-1(2H)one thiosemicarbazone (tetralone thiosemicarbazone) named 4a, was further studied. This TSC lacked virucidal effects on JUNV virions. Results from time of addition experiments and viral protein expression assays suggest that compound 4a inhibited a late stage in the replicative cycle of JUNV.