Nitrogen-Containing Fused-Heteroaromatic Compounds as Anti-Bovine Viral Diarrhea Virus (BVDV) Agents

Bovine viral diarrhea virus (BVDV) infection is distributed worldwide, and is responsible for a major loss in cattle leading to significant economic loss to producers. Although vaccines are used in some countries in an attempt to control the pestivirus disease, the degrees of success are variable. An alternative approach could be the use of anti-BVDV agents. Recently, a number of anti-BVDV compounds have been reported. However, there are no antiviral treatment options for controlling the pestivirus disease currently, and the emergence of BVDV strains resistant to antiviral compounds would be inevitable. Thus, development of anti-BVDV agents with a novel scaffold structure is needed. In addition, BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug research. Therefore, development of a novel scaffold for anti-BVDV agents and obtaining the structure-activity relationship (SAR) information would contribute to the development of novel anti-HCV agents. Under such circumstances, we performed structural development studies of anti-BVDV agents with a novel scaffold structure. As a result, we identified fused heteroaromatic structure as a superior thalidomide-derived scaffold for candidate drugs with potent anti-BVDV activity, by means of antiviral activity screening in Madin-Darby bovine kidney (MDBK) cells infected with BVDV. Among the compounds, 3,4,5-trimethyl-γ-carboline SK3M4M5M (44) possessed the most potent anti-BVDV activity with the EC50 (concentration causing 50% reduction of BVDV replication-induced cell destruction) value of 3.5 nM and low cytotoxicity. The process of the structural development and SAR studies are reviewed.