3 research outputs found
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(O<sub>2</sub>CCF<sub>3</sub>), 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 R<sup>6</sup> substituents on the 2(1<i>H</i>)-pyrazinone core and several inhibitors with improved
inhibitory potency down to <i>K</i><sub>i</sub> = 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
R<sup>6</sup> 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 IC<sub>50</sub> values and promising antituberculosis MIC values