Phenoxybenzenes and phenoxypyridines were prepared and tested for the effect of substituents on antipicornavirus activity. The most active compound, 2-(3, 4- dichlorophenoxy)-5-nitrobenzonitrile (8), demonstrated broad-spectrum antipicornavirus activity. Compound 8 and several analogues each given orally prior to and during infection protected mice against an otherwise lethal challenge with coxsackievirus A21.