A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub- micromolar affinity is reported. The benzimidazole'hit'1 with a KD~ 100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry- based screening methods. Further MS-assisted SAR (structure-activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA ...