Application of the Photoredox Coupling of Trifluoroborates and Aryl Bromides to Analog Generation Using Continuous Flow

A method for the coupling of aryl bromides with potassium alkyl trifluoroborates, via nickel/photoredox dual catalysis, has been developed for use in continuous flow. This operationally simple protocol is able to form C<i>sp</i>³–C<i>sp</i>² bonds with significantly reduced reaction times and a broader substrate scope than when conducted in batch. The utility of this method for rapid analog synthesis has been demonstrated by the synthesis of a small library of alkyl-substituted quinazolines

Synthesis of Cycloalkyl Substituted 7‑Azaindoles via Photoredox Nickel Dual Catalytic Cross-Coupling in Batch and Continuous Flow

An efficient photoredox/Ni dual catalytic C_sp²–C_sp³ cross-coupling protocol in a continuous-flow regime to synthesize a variety of regioisomeric cycloalkyl substituted 7-azaindoles has been developed. These transformations proceed efficiently under mild conditions (blue LED light irradiation at 30 °C over 40 min residence time in mixed solvent systems). Reactions are easy to perform and afford most of the desired 2-, 3-, 4-, 5-, and 6-cycloalkyl substituted 7-azaindoles in moderate-to-good yield

Synthesis of β‑Ketosulfonamides Derived from Amino Acids and Their Conversion to β‑Keto-α,α-difluorosulfonamides via Electrophilic Fluorination

β-Ketosulfonamides derived from Boc or Cbz-protected amino acids bearing hydrophobic side chains were prepared in good to excellent yield by treating <i>N</i>-allyl, <i>N</i>-alkyl methanesulfonamides with <i>n</i>-BuLi, followed by reaction of the resulting carbanion with methyl esters of <i>N</i>-protected l-amino acids. The analogous reaction using the dianion derived from an <i>N</i>-alkyl methanesulfonamide proceeded in much lower yield. Electrophilic fluorination of the β-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature for 15–60 min provided β-keto-α,α-difluorosulfonamides in good to excellent yields. The allyl protecting group could be removed in good yield using cat. Pd­(PPh)₃)₄ and dimethyl barbituric acid. When the fluorination reaction was performed with Cs₂CO₃ as base, β-ketosulfonamides derived from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides, while β-ketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-difluorosulfonamides

Synthesis of β‑Ketosulfonamides Derived from Amino Acids and Their Conversion to β‑Keto-α,α-difluorosulfonamides via Electrophilic Fluorination

β-Ketosulfonamides derived from Boc or Cbz-protected amino acids bearing hydrophobic side chains were prepared in good to excellent yield by treating <i>N</i>-allyl, <i>N</i>-alkyl methanesulfonamides with <i>n</i>-BuLi, followed by reaction of the resulting carbanion with methyl esters of <i>N</i>-protected l-amino acids. The analogous reaction using the dianion derived from an <i>N</i>-alkyl methanesulfonamide proceeded in much lower yield. Electrophilic fluorination of the β-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature for 15–60 min provided β-keto-α,α-difluorosulfonamides in good to excellent yields. The allyl protecting group could be removed in good yield using cat. Pd­(PPh)₃)₄ and dimethyl barbituric acid. When the fluorination reaction was performed with Cs₂CO₃ as base, β-ketosulfonamides derived from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides, while β-ketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-difluorosulfonamides

Three-dimensional neurophenotyping of adult zebrafish behavior: updates, achievements and future directions

<p>Three-dimensional reconstructions of zebrafish swimming paths (Cachat et al. 2011) are a new technique to discover novel, meaningful behavioral patterns evoked by different experimental manipulations. Compared to traditional 2D traces, 3D swim path reconstructions enable both macro-level (general) and micro-level (specific/repeated) analyses of potentially meaningful behavioral patterns, offering a complete picture of fish behavior that can be easily combined or re-analyzed. ‘Temporal’ 3D reconstructions, which plot horizontal (x) and vertical (y) spatial data across time (t), reflect zebrafish activity over testing time. ‘Spatial’ 3D reconstructions require two cameras to plot horizontal (x, front view), vertical (y, front view) and side-side (x or y, top view) data, depicting zebrafish 3D activity within the actual testing arena. These reconstructions are highly sensitive to anxiolytic, anxiogenic and hallucinogenic effects in adult zebrafish. For example, we have recently characterized unique movement profiles of ibogaine (a hallucinogen with psychedelic/dissociative properties) which reversed natural zebrafish behaviors, and whose comprehensive characterization would not have been possible without using 3D reconstructions (Cachat et al., 2012). We also applied Track3D, a supplement for EthoVision XT (Noldus IT, Netherlands) developed originally for insects, to adult zebrafish neurophenotyping. Our data represents the first successful application of Track3D in adult zebrafish, showing strong (R>0.07) significant correlation of automated behavioral endpoints with manual data. Track3D provided a precise calculation of movement parameters (i.e., distance traveled, velocity, angular velocity, path tortuosity) within 3D space, also offering accurate spatiotemporal integration of two-camera recordings. We are actively using the 3D-based reconstructions as a window into qualitative and quantitative descriptions of behavioral profiles of various psychotropic drugs. The spatiotemporal data generated from 3D approaches also permits the application of advanced moving object statistical techniques (e.g., movement pattern analysis) to identify and compare movement profiles of zebrafish under different experimental conditions, including testing anxiogenic/anxiolytic and hallucinogenic drugs, as well as identifying unique movement profiles for screening novel psychoactive compounds.</p

Design, Synthesis, and Structure–Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound <b>4</b>, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound <b>37</b> represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for <i>in vivo</i> experimentation

Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions

Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit <i>Mycobacterium tuberculosis</i> through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in <i>M. tuberculosis</i>. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (<i>K</i>_i ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 μM (1–2 μg/mL) against the H37Ra isolate of <i>M. tuberculosis</i>

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

Lomibuvir (<b>1</b>) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound <b>2</b>, a molecule with comparable potency and an improved physicochemical profile relative to <b>1</b>. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by <b>12f</b>, provided 3–5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure–activity relationships, <i>in vitro</i> ADME characterization, and <i>in vivo</i> evaluation of this novel series are discussed

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (<b>1</b>) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound <b>23</b>, a compound with comparable potency and improved physicochemical properties

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (<b>1</b>) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound <b>23</b>, a compound with comparable potency and improved physicochemical properties