The high functionality and complex three dimensional structure of RNA offers promise for the development of a wide range of RNA-targeting therapeutics. Previous studies of known RNA-friendly molecules reveal properties which promote RNA-small molecule interactions, such as distinct edges containing multiple hydrogen-bonding donors and acceptors, positively charged amino groups, opportunities for pi-stacking, and molecule rigidity. TAN 1057 is a natural dipeptide antibiotic thought to inhibit translation through interactions with ribosomal RNA. Modeling studies of the dihydropyrimidinone core of TAN 1057 show multiple potential interactions with each of the RNA bases. The synthesis of potential "RNA-friendly" small molecules was carried out using derivatives of the natural core of TAN 1057. Coupling of these derivative cores with various side groups containing "RNA-friendly" properties sought to promote further RNA-small molecule interactions. Three cores in addition to the natural core were synthesized and derivatized when possible, creating a small library of compounds to be tested against functional regions of RNA. Specifically, this work sought to target functional RNA within the hepatitis C virus and thymidylate synthase RNA, and structure activity relationships were explored

A class of dihydropyranobenzimidazole inhibitors was recently discovered that acts against the hepatitis C virus (HCV) in a new way, binding to the IRES-IIa subdomain of the highly conserved 5' untranslated region of the viral RNA and thus preventing the ribosome from initiating translation. However, the reported synthesis of these compounds is lengthy and low-yielding, the intermediates are troublesome to purify, and the route is poorly structured for the creation of libraries. We report a streamlined route to this class of inhibitors in which yields are far higher and most intermediates are crystalline. In addition, a key variable side chain is introduced late in the synthesis, allowing analogs to be easily synthesized for optimization of antiviral activity.