Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1.

Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space.

Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes.

Background: Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery.

A Mild Synthesis of Aryl Triflates Enabling the Late-Stage Modification of Drug Analogs and Complex Peptides.

We report the discovery of a straightforward protocol to convert phenols into the corresponding aryl triflates using 1-methyl-3-((trifluoromethyl)sulfonyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one in the presence of a fluoride source. This novel reagent can be handled without any precautions to exclude air or moisture making this method highly convenient. The reactions generally show very clean conversions within only a few minutes at room temperature.

Anticoagulation in COVID-19 patients - An updated systematic review and meta-analysis.

Background: Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial.

Material And Methods: This report updates our systematic review and random-effects meta-analysis on randomized controlled trials (RCTs) comparing standard prophylactic anticoagulation and intermediate or therapeutic anticoagulation in COVID-19 patients.

Advances in the design of new types of inhaled medicines.

Inhalation of small molecule drugs has proven very efficacious for the treatment of respiratory diseases due to enhanced efficacy and a favourable therapeutic index compared with other dosing routes. It enables targeted delivery to the lung with rapid onset of therapeutic action, low systemic drug exposure, and thereby reduced systemic side effects. An increasing number of pharmaceutical companies and biotechs are investing in new modalities-for this review defined as therapeutic molecules with a molecular weight >800Da and therefore beyond usual inhaled small molecule drug-like space.

Ivermectin for preventing and treating COVID-19.

Background: Ivermectin, an antiparasitic agent, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in early stages of infection. Currently, evidence on ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting.

Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction.

Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency.

Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors.

Inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-κB signaling, with the potential to treat B-cell lymphoma and autoimmune diseases. We describe the discovery and optimization of (1s,4s)-N,N'-diaryl cyclohexane-1,4-diamines, a novel series of allosteric MALT1 inhibitors, resulting in compound 8 with single digit micromolar cell potency. X-ray analysis confirms that this compound binds to an induced allosteric site in MALT1.

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies.

Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco-2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration.

Mechanism-Based Insights into Removing the Mutagenicity of Aromatic Amines by Small Structural Alterations.

Aromatic and heteroaromatic amines (ArNH) are activated by cytochrome P450 monooxygenases, primarily CYP1A2, into reactive -arylhydroxylamines that can lead to covalent adducts with DNA nucleobases. Hereby, we give hands-on mechanism-based guidelines to design mutagenicity-free ArNH. The mechanism of N-hydroxylation of ArNH by CYP1A2 is investigated by density functional theory (DFT) calculations.

Interactive Vibrotactile Feedback Enhances the Perceived Quality of a Surface for Musical Expression and the Playing Experience.

An advanced multi-touch sensor surface aimed at musical expression was recently equipped by the authors with interactive multi-point localized vibrotactile feedback. Using such interface, a subjective assessment was conducted that measured how the presence and type of vibration affect the perceived quality of the device and various attributes related to the playing experience. Two clearly distinct sound settings each with three vibrotactile feedback strategies were tested.

Mining Natural Products for Macrocycles to Drug Difficult Targets.

Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction, a particularly challenging target due to its highly polar binding site.

-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist's Toolbox.

Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, -trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of -trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties.

Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients.

Background: The antibacterial effect of antibiotics is linked to the free drug concentration. This study investigated the applicability of an ultrafiltration method to determine free plasma concentrations of beta-lactam antibiotics in ICU patients.

Methods: Eligible patients included adult ICU patients treated with ceftazidime (CAZ), meropenem (MEM), piperacillin (PIP)/tazobactam (TAZ), or flucloxacillin (FXN) by continuous infusion.

Determination of free clindamycin, flucloxacillin or tedizolid in plasma: Pay attention to physiological conditions when using ultrafiltration.

Pharmacokinetic/pharmacodynamic indices of anti-infective drugs should be referenced to free drug concentrations. In the present study, clindamycin, flucloxacillin and tedizolid have been determined in human plasma by HPLC-UV. The drugs were separated isocratically within 3-6 min on a C column using mixtures of phosphate buffer-acetonitrile of pH 7.

Determination of total or free cefazolin and metronidazole in human plasma or interstitial fluid by HPLC-UV for pharmacokinetic studies in man.

Cefazolin (CFZ) plus metronidazole (MTZ) is commonly used for perioperative antibiotic prophylaxis. An HPLC-UV method is described for the simultaneous determination of total or free cefazolin and metronidazole in human plasma or in microdialysate of subcutaneous tissue. Separation was performed isocratically using a reversed phase column and phosphate buffer/acetonitrile as mobile phase.

Feasibility of an 8-item questionnaire for early diagnosis of inflammatory bowel disease in primary care.

Aims: Diagnosis of inflammatory bowel disease (IBD) is often associated with a diagnostic delay. Although faecal calprotectin is a helpful screening tool, the widespread use in primary care (PC) may not be appropriate due to the low prevalence of IBD in this setting. To increase pretest probability for a positive calprotectin test, an 8-item questionnaire (CalproQuest) was tested for its feasibility and acceptability in PC.

Determination of total and free ceftolozane and tazobactam in human plasma and interstitial fluid by HPLC-UV.

Ceftolozane/tazobactam is a new cephalosporin/beta-lactamase inhibitor combination. An HPLC-UV method is described for the determination of total and free ceftolozane and tazobactam in human plasma and in microdialysate of subcutaneous tissue, respectively. Separation was performed using a reversed-phase column with phosphate buffer/acetonitrile as eluent and photometric detection at 260 nm (ceftolozane) or 220 nm (tazobactam).

Toward the Design of Molecular Chameleons: Flexible Shielding of an Amide Bond Enhances Macrocycle Cell Permeability.

A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-π interaction. This resulted in increased cell permeability, suggesting that NH-π interactions may be used in the design of molecular chameleons.

Concise total synthesis of (+)-asperazine A and (+)-pestalazine B.

The highly convergent total synthesis of dimeric diketopiperazine alkaloids (+)-asperazine A and (+)-pestalazine B is described. A critical aspect of our expedient route was the development of a directed regio- and diastereoselective C3-N1' coupling of complex tetracyclic diketopiperazine components. This late-stage heterodimerization reaction was made possible by design of tetracyclic diketopiperazines that allow C3-carbocation coupling of the electrophilic component to the N1' locus of the nucleophilic fragment.

Beyond wilderness: towards an anthropology of infrastructure and the built environment in the Russian North.

Public and academic discourses about the Polar regions typically focus on the so-called natural environment. While, these discourses and inquiries continue to be relevant, the current article asks the question how to conceptualize the on-going industrial and infrastructural build-up of the Arctic. Acknowledging that the "built environment" is not an invention of modernity, the article nevertheless focuses on large-scale infrastructural projects of the twentieth century, which marks a watershed of industrial and infrastructural development in the north.