Relying on a broadened anti-myxovirus target spectrum as the main selection criterion in secondary screening assays, we have mined results of a recently completed high throughput chemical library screen [19] to identify hit candidates with a possible hostdirected mechanism of action. This has yielded a compound class with broad anti-viral activity, which was subjected to synthetic scaffold optimization, quantification of active concentrations for a select group of clinically relevant ortho-and paramyxovirus family members, testing against a panel of exposed host cells of different species origin, and characterization of the compound-induced point-of-arrest in viral life cycle progression. Viral adaptation to growth in the presence of inhibitor has been employed to compare escape rates from inhibition by this new compound class with those from a well-characterized, pathogen-directed antiviral.