In this study we report the design, synthesis, and activity against bovine viral diarrhea virus (BVDV) of a novel series of acridone derivatives. BVDV is responsible for major losses in cattle. The virus is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. Some of the synthesized acridones elicited selective anti-BVDV activity with EC(50) values ranging from 0.4 to 4 microg/mL and were not cytotoxic at concentrations that were 25- to 200-fold higher (CC(50) >100 microg/mL). It was proven that the most potent acridone derivative 10 was able to not only protect cells from virus-induced cytopathic effect but also reduce the production of infectious virus and extracellular viral RNA. Furthermore, compound 10, as well as a number of other analogues, inhibited HCV replication to some extent. However, there was no direct correlation between anti-BVDV and anti-HCV activity. Thus, the acridone scaffold, when appropriately functionalized, can yield compounds with selective activity against pestiviruses and related viruses such as the HCV.