SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain.

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 approximately 100 microM 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 construct.

Optimizing the antibacterial activity of a lead structure discovered by "SAR by MS" technology.

We report on lead optimization of a compound that was originally discovered to bind bacterial 23S rRNA near the L11 binding site and inhibit translation in vitro, but lacked detectable antibacterial activity. In this study, we were able to generate compounds with antibacterial activity against Gram-negative and Gram-positive pathogens, including a methicillin-resistant S. aureus strain.

Biaryl guanidine inhibitors of in vitro HCV-IRES activity.

A structure-activity relationship analysis was carried out on a high-throughput small molecule screening lead for HCV-IRES translation inhibition. The study led to the identification of a guanidine-based structure with low microM inhibitory activity.

Antibacterial activity of quinolone-macrocycle conjugates.

Novel quinolone-macrocycle conjugates displayed submicromolar antibacterial activity against Escherichia coli and Staphylococcus aureus bacterial strains. An analogous open-chain structure was not active at 100 microM against the same pathogenic strains.

New inhibitors of bacterial protein synthesis from a combinatorial library of macrocycles.

A mixture-based combinatorial library of 14-membered macrocycles was synthesized to target ribosomal RNA and uncover a new class of antibacterial agents. High-throughput screening identified a macrocyclic mixture that inhibited cell-free-coupled transcription/translation in Escherichia coli-derived extracts, with an IC(50) value in the 25-50 microM range. In a follow-up library of 64 single macrocycles, 8 gave IC(50) values ranging from 12 to 50 microM in the cell-free protein synthesis inhibition assay.