Design and synthesis of privileged scaffolds for targeting RNA

A series of novel benzoxazoles was designed and synthesized with the goal of binding to subdomain IIa of the Hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA and inhibiting viral translation. The benzoxazoles were prepared with fundamental traits which bias these ligands for interaction with RNA. The benzoxazoles were constructed around a recognition element contained in a known subdomain IIa binding ligand that forms discrete hydrogen bonds to the RNA target. This motif within a novel benzoxazole core was anticipated to act as a molecular anchor which orients various substituents, allowing for the exploration of the chemical environment in the subdomain IIa binding cavity. The novel ligands were evaluated by a FRET assay and an in vitro translation assays to determine binding affinity and target inhibition. Structure activity relationships of the substitution patterns were explored. Functional elements which conferred activity were combined around a common benzoxazole scaffold with the goal of creating improved inhibitors.