Synthesis, antiviral evaluation and molecular docking studies of N4-aryl substituted/unsubstituted thiosemicarbazones derived from 1-indanones as potent anti-bovine viral diarrhea virus agents.
A series of N4-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N4 position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50=2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis. In a previous study, the thiosemicarbazone of 5,6-dimethoxy-1-indanone (5,6-TSC) was characterized as a non-nucleoside inhibitor (NNI) of the BVDV RNA-dependent RNA polymerase. In the present work, cross-resistance assays were performed with the most active compounds. Such studies were carried out on 5,6-TSC resistant BVDV (BVDV-TSCr T1) carrying mutations in the viral polymerase. This BVDV mutant was also resistant to compound 15. Molecular docking studies and MM/PBSA calculations were performed to assess the most active derivatives at the 5,6-TSC viral polymerase binding site. The differences in the interaction pattern and the binding affinity of derivative 15 either to the wild type or BVDV-TSCr T1 polymerase were key factors to define the mode of action of this compound.
['Soraires Santacruz|María C|MC|', 'Fabiani|Matías|M|', 'Castro|Eliana F|EF|', 'Cavallaro|Lucía V|LV|', 'Finkielsztein|Liliana M|LM|']
D000818:Animals D000998:Antiviral Agents D002417:Cattle D002460:Cell Line D001908:Diarrhea Viruses, Bovine Viral D007189:Indans D062105:Molecular Docking Simulation D013057:Spectrum Analysis D013329:Structure-Activity Relationship D013882:Thiosemicarbazones D010948:Viral Plaque Assay D014779:Virus Replication
Molecular docking Thiosemicarbazones RNA-dependent RNA polymerase Antiviral activity Antiviral resistance Bovine viral diarrhea virus (BVDV)