Silver N-heterocyclic biscarbene complexes: Potent inhibitors of thioredoxin reductase with anticancer activity in vitro and in vivo.

Silver N-heterocyclic carbene (NHC) complexes are known to form biscarbene species from monocarbene analogs in protic polar solvents. However, the effect of the respective species of silver NHC complexes on their biological activity against bacteria or cancer cells has not been systematically explored, either in vitro or in vivo. The direct and simple conversion of monocarbene silver N-heterocyclic carbene (NHC) halide complexes (NHC)AgX, (X= Cl, Br) 1a/b - 5a/b to their biscarbene analogues (NHC)2AgX 1c/d - 5c/d is reported.

Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation.

Protective effects of Euphorbia heterophylla against testicular degeneration in streptozotocin-induced diabetic rats in relation to phytochemical profile.

Background: Diabetes mellitus (DM) poses a major risk to human health due to an array of implications, one of which is a detrimental effect on the testicular and reproductive functions. Euphorbia heterophylla is widely recognized for its medicinal properties worldwide.

Methods And Findings: The objective of this study was to profile E.

First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer.

Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes.

Histamine H receptor blockade alleviates neuropathic pain through the regulation of glial cells activation.

Neuropathic pain is a disorder affecting the somatosensory nervous system. However, this condition is also characterized by significant neuroinflammation, primarily involving CNS-resident non-neuronal cells. A promising target for developing new analgesics is histamine H receptor (HR); thus, we aimed to determine the influence of a novel HR antagonist/inverse agonist, E-98 (1-(7-(4-chlorophenoxy)heptyl)-3-methylpiperidine), on pain symptoms and glia activation in model of neuropathic pain in male mice (chronic constriction injury to the sciatic nerve).

2-Phenylbenzothiazoles featuring heteroaryl sulfonamide end-capping substructures as developable mPGES-1 inhibitors.

The inhibition of human microsomal prostaglandin E (PGE) synthase-1 (mPGES-1) is a promising therapeutic modality for developing next-generation anti-inflammatory medications. In this study, we present novel 2-phenylbenzothiazole derivatives featuring heteroaryl sulfonamide end-capping substructures as inhibitors of human mPGES-1, with IC values in the range of 0.72-3.

Thiol-Reactive or Redox-Active: Revising a Repurposing Screen Led to a New Invalidation Pipeline and Identified a True Noncovalent Inhibitor Against Papain-like Protease from SARS-CoV-2.

The SARS-CoV-2 papain-like protease PLpro has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its ability to antagonize the host immune response. Targeting the PLpro function is recognized as a promising mechanism to modulate viral replication, while supporting host immune responses. However, the development of PLpro-specific inhibitors remains challenging.

Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release.

Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors.

Pyrazinyl-Substituted Aminoazoles as Covalent Inhibitors of Thrombin: Synthesis, Structure, and Anticoagulant Properties.

This study presents a novel series of -acylated 1,2,4-triazol-5-amines and 1-pyrazol-5-amines, featuring a pyrazin-2-yl moiety, developed as covalent inhibitors of thrombin. These compounds demonstrated potent inhibitory activity, with derivatives and achieving IC values as low as 0.7 and 0.

Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.

The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.

Structural and Dynamic Assessment of Disease-Causing Mutations for the Carnitine Transporter OCTN2.

Primary carnitine deficiency (PCD) is a rare autosomal recessive genetic disorder caused by missense mutations in the SLC22A5 gene encoding the organic carnitine transporter novel type 2 (OCTN2). This study investigates the structural consequences of PCD-causing mutations, focusing on the N32S variant. Using an alpha-fold model, molecular dynamics simulations reveal altered interactions and dynamics suggesting potential mechanistic changes in carnitine transport.

Expanding the Chemical Space of Reverse Fosmidomycin Analogs.

Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for , , and that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin.

Diketopiperazine/piperidine alkaloid as a potential broad-spectrum coronaviral entry inhibitor identified by supercomputer-based virtual screening from a large natural product-based library.

The COVID-19 pandemic has underscored the urgent need for antiviral agents capable of targeting a broad range of coronaviruses, including emerging variants of SARS-CoV-2. While vaccines have been pivotal, the search for drugs that can prevent viral entry into host cells remains crucial, especially against evolving viral forms and other coronaviruses. In this study, we investigated natural products as a source of antiviral agents, focusing on their potential to block the spike protein's receptor-binding domain (RBD).

Comparative Study of Iminodibenzyl and Diphenylamine Derivatives as Hole Transport Materials in Inverted Perovskite Solar Cells.

Perovskite solar cells (PSCs) have recently achieved over 26% power conversion efficiency, challenging the dominance of silicon-based alternatives. This progress is significantly driven by innovations in hole transport materials (HTMs), which notably influence the efficiency and stability of PSCs. However, conventional organic HTMs like PTAA, although highly efficient, suffer from thermal degradation, moisture ingress, and high cost.

Development of the First-in-Class FEM1B-Recruiting Histone Deacetylase Degraders.

Targeted protein degradation (TPD) represents a promising alternative to conventional occupancy-driven protein inhibition. Despite the existence of more than 600 E3 ligases in the human proteome, so far only a few have been utilized for TPD of histone deacetylases (HDACs), which represent important epigenetic anticancer drug targets. In this study, we disclose the first-in-class Fem-1 homologue B (FEM1B)-recruiting HDAC degraders.

Identification of a Chemical Probe for BLT2 Activation by Scaffold Hopping.

The leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor, which is endogenously activated by 12()-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). BLT2 is gaining attention as a potential therapeutic target involved in various pathologies including diabetic wound healing, ophthalmic diseases, and colitis. However, validation of BLT2 as drug target requires chemical probes and pharmacological tools which will allow for application in vivo.

4-O-Methylglucuronoxylan from Hygrophila Ringens var. Ringens Seeds: Chemical Composition and Anti-Inflammatory Activity.

Hygrophila ringens var. ringens is a medicinal plant of the Acanthaceae family. A soluble polysaccharide is extracted from H.

Interpretable Deep-Learning p Prediction for Small Molecule Drugs via Atomic Sensitivity Analysis.

Machine learning (ML) models now play a crucial role in predicting properties essential to drug development, such as a drug's logscale acid-dissociation constant (p). Despite recent architectural advances, these models often generalize poorly to novel compounds due to a scarcity of ground-truth data. Further, these models lack interpretability.

Molecular dynamics simulations to decipher the hotspots at the allosteric site of human 5-lipoxygenase.

Human 5-lipoxygenase (LOX) is a non-heme, Fe-containing LOX which catalyses the conversion of arachidonic acid (AA) to leukotriene A (LTA). LTA is subsequently converted to cysteinyl-LTs and LTB that cause bronchoconstriction and act as chemotactic and chemokinetic agent on human leukocytes, respectively. Leukotrienes play significant roles in inflammation in asthma, cardiovascular diseases, allergic rhinitis, atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and many more.

Photocatalytic Direct Borylation of Benzothiazole Heterocycles via a Triplet Activation Strategy.

Boron compounds are widely employed in organic chemistry, pharmaceuticals, and materials science. Among them, borylated heterocycles serve as versatile synthons for the construction of new C-C or C-heteroatom bonds via coupling or radical processes. Such methods for direct C-H borylation reactions are of high synthetic value to reduce the number of synthetic steps and the amount of waste and to improve efficiency.

Imaging the Ultrastructure of Isolated Peptidoglycan Sacculi from Rod-Shaped J99 Cells by Atomic Force Microscopy.

Peptidoglycan is the basic structural polymer of the bacterial cell wall and maintains the shape and integrity of single cells. Despite years of research conducted on peptidoglycan's chemical composition, the microscopic elucidation of its nanoscopic architecture still needs to be addressed more thoroughly to advance knowledge on bacterial physiology. Apart from the model organism , ultrastructural imaging data on the murein architecture of Gram-negative bacteria is mostly missing today.

The Diverse Binding Modes Explain the Nanomolar Levels of Inhibitory Activities Against 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase from Exhibited by Reverse Hydroxamate Analogs of Fosmidomycin with Varying -Substituents.

It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against DXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the -phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of DXR.

BenchAMRking: a Galaxy-based platform for illustrating the major issues associated with current antimicrobial resistance (AMR) gene prediction workflows.

Background: The Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) networks 'Seq4AMR' and 'B2B2B AMR Dx' were established to promote collaboration between microbial whole genome sequencing (WGS) and antimicrobial resistance (AMR) stakeholders. A key topic discussed was the frequent variability in results obtained between different microbial WGS-related AMR gene prediction workflows. Further, comparative benchmarking studies are difficult to perform due to differences in AMR gene prediction accuracy and a lack of agreement in the naming of AMR genes (semantic conformity) for the results obtained.

Novel Drug Delivery Particles Can Provide Dual Effects on Cancer "Theranostics" in Boron Neutron Capture Therapy.

Boron (B) neutron capture therapy (BNCT) is a novel non-invasive targeted cancer therapy based on the nuclear capture reaction B (n, alpha) Li that enables the death of cancer cells without damaging neighboring normal cells. However, the development of clinically approved boron drugs remains challenging. We have previously reported on self-forming nanoparticles for drug delivery consisting of a biodegradable polymer, namely, "AB-type" Lactosome nanoparticles (AB-Lac particles)- highly loaded with hydrophobic B compounds, namely -Carborane (Carb) or 1,2-dihexyl--Carborane (diC6-Carb), and the latter (diC6-Carb) especially showed the "molecular glue" effect.