Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV

Bovine viral diarrhea virus (BVDV) is a major pathogen of cattle with a great economic impact. The identification of antivirals for the treatment of BVDV infections and outbreak control is relevant. After drug-modulation of 5,6-TSC, a compound previously identified as a non-nucleoside inhibitor (NNI) of BVDV RNA-polymerase (RdRp), a series of thiosemicarbazones (TSC) and N4-arylthiosemicarbazones derived from 1-indanones was synthesized. Two compounds with higher anti-BVDV activity were identified: N4-(p-nitrophenyl)-TSC derived from 5,6-dimethoxy-1-indanone (N4-TSC) and TSC derived from 6-nitro-1-indanone (6NO2-TSC), which were active against BVDV strains from different genotypes and biotypes and inactive against other RNA viruses. It was demonstrated that these compounds act in intermediate stages of the viral replication cycle. Particularly, N4-TSC acts by blocking viral RNA synthesis, and by means of BVDV resistance selection (N4-TSCR), viral RdRp was identified as the molecular target. Docking and molecular dynamics studies showed that the mutations N264D and A392E, found in N4-TSCR viruses, alter the interactions of N4-TSC with RdRp and are responsible for antiviral resistance. ; Fil: Fabiani, Matias. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina ; El virus de la diarrea viral bovina (BVDV) es un patógeno importante del ganado bovino de gran impacto económico, por lo que la identificación de antivirales para el tratamiento de las infecciones y control de los brotes por BVDV resulta de interés. Mediante fármaco-modulación de 5,6-TSC, un compuesto previamente identificado como un inhibidor no nucleosídico (INN) de la ARN-polimerasa (RdRp) de BVDV, se sintetizaron una serie de tiosemicarbazonas (TSC) y N4-ariltiosemicarbazonas derivadas de 1-indanonas. A partir de esto, en este trabajo de tesis se identificaron dos compuestos con mayor actividad anti-BVDV: N4-(p-nitrofenil)-TSC derivada de la 5,6-dimetoxi-1-indanona (N4-TSC) y la TSC derivada de 6-nitro-1-indanona ...