Benzodiazepinones and cyclopropylquinazolinamines were designed and synthesized with the goal of creating ligands for the subdomain IIa of the hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA and thereby inhibiting viral translation. The heterocyclic scaffolds were designed using insight into molecular recognition of the RNA target by previously discovered synthetic and natural ligands. The novel benzodiazepinones and cyclopropylquinazolinamines were evaluated for RNA target binding by a previously developed FRET assay.