Initial performance evaluation of a spotted array Mobile Analysis Platform (MAP) for the detection of influenza A/B, RSV, and MERS coronavirus.

Clinical samples were evaluated with the Mobile Analysis Platform (MAP) to determine platform performance for detecting respiratory viruses in samples previously characterized using clinical reverse transcriptase polymerase chain reaction assays. The percent agreement between MAP and clinical results was 97% for influenza A (73/75), 100% (21/21) for influenza B, 100% (6/6) for respiratory syncytial virus (RSV), and 80% (4/5) for negative specimens. The approximate limit of detection of the MAP was 30 copies/assay for RSV and 1500 copies/assay for Middle East respiratory syndrome coronavirus.

An efficient synthesis of gougerotin and related analogues using solid- and solution-phase methodology.

The first solid-phase synthesis of the natural product gougerotin has been accomplished. The synthetic route is versatile and allows for diversification at position C-4 of the heterocycle, C-6' of the sugar ring, and both residues of the peptidic moiety at N-4' in a parallel fashion. [structure: see text]

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. Some of the macrocycles were screened in a translation inhibition assay, and IC(50) values generally paralleled those obtained in the uncoupled transcription/translation assay. Additional analogues were prepared in a preliminary structure-activity relationship study, and more potent macrocycles were identified with low micromolar activity (IC(50) values = 2-3 microM). Some of these macrocycles displayed antibacterial activity against lipopolysaccharide mutant E. coli bacterial cells (IC(50) values = 12-50 microM).

SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets.

A technique for lead discovery vs RNA targets utilizing mass spectrometry (MS) screening methods is described. The structure-activity relationships (SAR) derived from assaying weak binding motifs allows the pharmacophores discovered to be elaborated via "SAR by MS" to higher affinity ligands. Application of this strategy to a subdomain of the 23S rRNA afforded a new class of compounds with functional activity.

Synthesis and biological evaluations of novel benzimidazoles as potential antibacterial agents.

A series of novel benzimidazole derivatives were synthesized via parallel solution-phase chemistry. Many of these compounds were found to inhibit the growth of Staphylococcus aureus and Escherichia coli. Several analogues exhibited low micromolar minimal inhibitory concentrations (MIC) against both Gram-positive and Gram-negative bacteria of clinical relevance and could serve as leads for further optimizations for antibacterial research.

Identification of 2-aminobenzimidazole dimers as antibacterial agents.

The preparation and evaluation of 2-aminobenzimidazole dimers as antibacterial agents is described. Biological screening of the dimers indicated that compounds with multiple chloro substituents possessed optimal antibacterial 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.

2-piperidin-4-yl-benzimidazoles with broad spectrum antibacterial activities.

A series of 2-piperidin-4-yl-benzimidazoles were synthesized and evaluated for antibacterial activities. Certain compounds inhibit bacterial growth with low micromolar minimal inhibitory concentration (MIC). These benzimidazoles are effective against both Gram-positive and Gram-negative bacteria of clinical importance, particularly enterococci, and represent a new class of potential antibacterial agents.

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.

Aryl urea analogs with broad-spectrum antibacterial activity.

The preparation and evaluation of novel aryl urea analogs as broad-spectrum antibacterial agents is described. Numerous compounds showed low micromolar minimum inhibitory concentrations (MIC) against both Gram-positive and Gram-negative bacteria. Selected analogs also exhibited in vivo efficacy in a lethal murine model of bacterial septicemia.