Synthesis, antiviral evaluation and molecular docking studies of N 4 -aryl substituted/unsubstituted thiosemicarbazones derived from 1-indanones as potent anti-bovine viral diarrhea virus agents

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 15; p. 4055
• Main Authors: Soraires Santacruz, María C, Fabiani, Matías, Castro, Eliana F, Cavallaro, Lucía V, Finkielsztein, Liliana M
• Format: Journal Article
• Language: English
• Published: England 01.08.2017
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cattle; Cell Line; Diarrhea Viruses, Bovine Viral - drug effects; Diarrhea Viruses, Bovine Viral - physiology; Indans - chemistry; Molecular Docking Simulation; Spectrum Analysis - methods; Structure-Activity Relationship; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Viral Plaque Assay; Virus Replication - drug effects; Bovine viral diarrhea virus (BVDV); Antiviral resistance; RNA-dependent RNA polymerase; Thiosemicarbazones; Antiviral activity; Molecular docking
• ISSN: 1464-3391

A series of N -arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N 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 (EC =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-TSC 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-TSC T1 polymerase were key factors to define the mode of action of this compound.