On-Water Synthesis of Biaryl Sulfonyl Fluorides

Herein, we report an efficient, ligand-free, and additive-free Suzuki–Miyaura coupling that is compatible with the aromatic sulfonyl fluoride functional group. The protocol proceeds at room temperature, on water, and offers facile access to a wide range of biaryl sulfonyl fluorides as bioorthogonal “click” reagents

The downfall of TBA-354 – a possible explanation for its neurotoxicity <i>via</i> mass spectrometric imaging

<p>1. TBA-354 was a promising antitubercular compound with activity against both replicating and static <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research.</p> <p>2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw).</p> <p>3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the <i>C</i>_max at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain.</p> <p>4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.</p

A Synthesis of “Dual Warhead” β‑Aryl Ethenesulfonyl Fluorides and One-Pot Reaction to β‑Sultams

Herein, we report an operationally simple, ligand- and additive-free oxidative boron-Heck coupling that is compatible with the ethenesulfonyl fluoride functional group. The protocol proceeds at room temperature with chemoselectivity and <i>E</i>-isomer selectivity and offers facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we demonstrate a “one-pot click” reaction to directly transform the products to aryl-substituted β-sultams

A comparative modeling and molecular docking study on <i>Mycobacterium tuberculosis</i> targets involved in peptidoglycan biosynthesis

<p>An alarming rise of multidrug-resistant <i>Mycobacterium tuberculosis</i> strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in <i>M. tuberculosis</i> are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 <i>M. tuberculosis</i> strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected <i>M. tuberculosis</i> targets involved in peptidoglycan biosynthesis.</p

Lysine Scanning of Arg₁₀–Teixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues

Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg₁₀–teixobactin as a reference, where the nonproteinogenic residue l-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity

Synthesis and Biological Evaluation of a Teixobactin Analogue

The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual l-<i>allo</i>-enduracididine residue by the naturally occurring l-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry