Synthesis of 3‑Substituted Aryl[4,5]isothiazoles through an All-Heteroatom Wittig-Equivalent Process

Extending the previous use of <i>tert</i>-butyl sulfoxide as the sulfinyl source, intramolecular sulfinylation of sulfonamides was successfully performed. The resulting sulfinimides were not isolated and instead were believed to go through an all-heteroatom Wittig-equivalent process to eventually afford aryl­[4,5]­isothiazoles in high yields

Thermolysis-Induced Two- or Multicomponent Tandem Reactions Involving Isocyanides and Sulfenic-Acid-Generating Sulfoxides: Access to Diverse Sulfur-Containing Functional Scaffolds

Direct reaction of isocyanides with some sulfenic-acid-generating sulfoxides led to the effective formation of the corresponding thiocarbamic acid <i>S</i>-esters in good to high yields. A multicomponent reaction involving isocyanide, sulfoxide, and a suitable nucleophile has also been developed, providing ready access to a diverse range of sulfur-containing compounds, including isothioureas, carbonimidothioic acid esters, and carboximidothioic acid esters

Improving Carbene–Copper-Catalyzed Asymmetric Synthesis of α‑Aminoboronic Esters Using Benzimidazole-Based Precursors

By using a benzimidazole core and N-substitutions to tune the electronic properties of the corresponding N-heterocyclic carbenes, a one-pot protocol for efficient synthesis of α-aminoboronic esters without the need of a glovebox was developed in this work. The starting materials for the transformation can also be extended from aldehydes to ketones. An alternative protocol with short reaction time using preformed carbene–copper chloride is also described

Urea-Based Inhibitors of Trypanosoma brucei Methionyl-tRNA Synthetase: Selectivity and in Vivo Characterization

Urea-based methionyl-tRNA synthetase inhibitors were designed, synthesized, and evaluated for their potential toward treating human African trypanosomiasis (HAT). With the aid of a homology model and a structure–activity-relationship approach, low nM inhibitors were discovered that show high selectivity toward the parasite enzyme over the closest human homologue. These compounds inhibit parasite growth with EC₅₀ values as low as 0.15 μM while having low toxicity to mammalian cells. Two compounds (<b>2</b> and <b>26</b>) showed excellent membrane permeation in the MDR1-MDCKII model and encouraging oral pharmacokinetic properties in mice. Compound <b>2</b> was confirmed to enter the CNS in mice. Compound <b>26</b> had modest suppressive activity against Trpanosoma brucei rhodesiense in the mouse model, suggesting that more potent analogues or compounds with higher exposures need to be developed. The urea-based inhibitors are thus a promising starting point for further optimization toward the discovery of orally available and CNS active drugs to treat HAT

TEM analysis of <i>N. caninum</i>-infected HFF cultures treated for 3 days, with 2.5 μM of inhibitor 1294 added at 2 h post-infection.

<p>A and B show micrographs of more or less densely packed parasitophorous vacuoles containing numerous tachyzoites without obvious alterations. C and D show a representative example of a vacuole delineated by a parasitophorous vacuole membrane (pvm) containing parasites displaying a large cytoplasmic mass and aberrant overall morphology. The boxed area in C is enlarged in D, exhibiting the presence of the pvm and rhoptry-like organelles (rho). In many instances, as seen in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092929#pone-0092929-g005" target="_blank">Figure 5E and F</a>, parasitophorous vacuoles contain several parasites exhibiting clear signs of metabolic impairment such as cytoplasmic vacuolization (vac) and electron-dense inclusions (inc). (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092929#pone-0092929-g005" target="_blank">Figure 5E, F</a>). Note that in C–F the matrix has lost its characteristic tubular network structure and is now formed of either granular material or possibly membranous material (C, D), or is even largely missing (E. F). Bars in A = 1 μm; B = 0.9 μm; C = 0.75 μm, D = 0.35 μm; E = 0.3 μm; F = 0.3 μm.</p

The simultaneous binding of Chem 1433 and AMPPCP.

<p>(A) The structure of <i>Tb</i>MetRS•<b>Chem 1433</b>•AMPPCP shown with the difference electron density calculated by omitting <b>Chem 1433</b> and AMPPCP, contoured at 3σ (gray is positive density, red is negative density). (B) Residues around 4.5 Å radius of AMPPCP is shown in stick model (light pink) with <b>Chem 1433</b> (deep purple) and AMPPCP (pale green) shown in ball and stick model. Possible hydrogen bonds between AMPPCP and <i>Tb</i>MetRS are shown with a dashed line. Crucially, the secondary amine in the linker of <b>Chem 1433</b> forms a strong hydrogen bond with a β-phosphate oxygen in AMPPCP (2.6 Å). (C) Superposition of <i>Tb</i>MetRS•<b>Chem 1433</b>•AMPPCP and <i>Tb</i>MetRS•MAMP (PDB: 4EG3, protein not depicted) show that the AMP moiety of MAMP (cyan) binds, on average, approximately 1.5 Å deeper into the ribose and adenine pockets (red arrow).</p

Typical binding mode of an UBI to <i>Tb</i>MetRS.

<p>(A) The structure of <i>Tb</i>MetRS•<b>Chem 1433</b> is used as the prototypic complex to depict the binding mode of the UBIs in which the R1 moiety binds to the EMP and urea-R2 moiety binds to the AP. R1 and urea-R2 moieties are connected by the <i>N</i>-methylpropanamine linker, which is mostly solvent exposed. <b>Chem 1433</b> is shown in ball and stick model in deep purple. <i>Tb</i>MetRS is shown in surface representation in light pink with residues within a 4.5 Å radius from <b>Chem 1433</b> as stick model in light pink. Also see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002775#pntd.0002775.s003" target="_blank">Figure S3</a> for interactions between <b>Chem 1433</b> and <i>Tb</i>MetRS in the EMP and the AP. (B) Binding of inhibitor is accompanied by movement of multiple residues in the active site compared to the Met-bound M-state (PDB code 4EG1). In the EMP, two subpockets, the EMP-S and the EMP-E, can be discerned. Both subpockets are lined mostly by hydrophobic residues, some shown in stick model in light pink. Superposition of <i>Tb</i>MetRS•Met complex (not shown) onto <i>Tb</i>MetRS•<b>Chem 1433</b> (light pink) showed that Met occupies the EMP-S with the sulfur atom (marked as yellow cross) occupying essentially the same position as one of the <i>meta</i>-Cl in <b>Chem 1433</b>. Val473, Trp474 and Phe522 moved significantly to form the EMP-E. Also see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002775#pntd.0002775.s003" target="_blank">Figure S3A</a> for further details of the interactions within the EMP.</p

5‑Fluoroimidazo[4,5‑<i>b</i>]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors

Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo­[4,5-<i>b</i>]­pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy

Interactions in the AP.

<p>Stereo pairs showing interaction between <b>Chem 1433</b> (ball and stick model, deep purple) and protein residues (stick model, light pink) within 4.5 Å radius of the inhibitor. (A) In the AP, the near-planar urea-R2 group is sandwiched in between the ‘walls’ formed by the similarly planar features of Tyr250 (side chain) and His289-Gly290 (peptide unit) on one side, with Val473 (side chain) and Tyr472-Val473 (peptide unit) on the other side (all boxed in gray shade). (B) The urea moiety forms crucial hydrogen bonds with Asp287, a strictly conserved residue among all MetRS. The secondary amine in the linker is bound to a water molecule (sphere, black) which in turn is hydrogen-bonded to the conserved Asp287 and the carbonyl oxygen of Ile248. Also see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002775#pntd.0002775.s003" target="_blank">Figure S3B</a> for further details of the interactions within the AP.</p

A superposition of <i>Bm</i>MetRS (PDB ID 4PLY2 Chain B) and <i>Tb</i>MetRS (PDB ID 4MVW Chain) bound to compound 1433.

<p>A key difference is the interaction of <i>Bm</i>MetRS Phe213 which is functionally equivalent to Leu456 in <i>Tb</i>MetRS but led to different protein geometry. The <i>Tb</i>MetRS structure is shown in blue and the 2 different residues in orange.</p