Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates

A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O₂CCF₃), 6-methyl-2,2′-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields

Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R⁶ substituents on the 2­(1<i>H</i>)-pyrazinone core and several inhibitors with improved inhibitory potency down to <i>K</i>_i = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R⁶ substituents were found to have a major influence on solubility, metabolic stability, and cell permeability

Trisubstituted Imidazoles as <i>Mycobacterium tuberculosis</i> Glutamine Synthetase Inhibitors

<i>Mycobacterium tuberculosis</i> glutamine synthetase (<i>Mt</i>GS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of <i>Mt</i>GS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-<i>tert</i>-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of <i>Mt</i>GS inhibitors with submicromolar IC₅₀ values and promising antituberculosis MIC values