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The angiotensin II type 2 receptor (AT₂R) is part of the renin-angiotensin aldosterone system and modulates central nervous and cardiovascular functions. During various pathological conditions the receptor is upregulated to exert vasodilating, anti-inflammatory, and neuroprotective functions, and therefore represents a promising drug-target. As part of our continuous exploration of agonist and antagonist ligands binding the AT₂R, a virtual screening campaign of an in-house library of ∼82,000 compounds were performed. Several pharmacophores from known AT₂R ligands were constructed, and in combination with the structural information from an AT₂R homology model, we employed a ligand-based approach to identify new ligands with potential for high affinity to the receptor. Fifty hits were identified and tested in vitro, of which ten compounds, representing five scaffold clusters, were found to bind the AT₂R. These clusters were validated via a hit expansion, where one of these hits, the first novel class of small molecule AT₂R ligand identified in many years, was then selected for further exploration. Through structure-activity relationships studies, one ligand (compound 15a-(S,S)) with sub-micromolar AT₂R affinity (K_i = 140 nM) was identified. The ligand also displayed a favorable in vitro profile; low metabolic clearance, good permeability, and fair solubility. Preliminary in vivo pharmacokinetic studies in mice revealed a good systemic exposure of the compound, with an estimated half-life of approximately six hours. The structure of compound 15a-(S,S) differs significantly from all other previously reported AT₂R ligands and can serve as a prototype and starting point for further AT₂R ligand optimization, and investigation into its agonistic, antagonistic or other functions.

A series of 2-substituted methylene imidazolephenylthiophene and tert-butylimidazolyl acetylphenylthiophene sulfonylcarbamate and sulfonamide derivatives were synthesized and assessed as AT₂R ligands. Substitution at this position of the phenyl ring, located between the thiophenyl and the linked imidazolyl substituent, has not previously been explored and unexpectedly resulted in significantly enhanced affinity for some of the new inhibitors. Introduction of a methyl group at the 2-position of the phenyl ring was found to markedly increase binding affinity to the AT₂R, as demonstrated across three different ligand classes. Binding affinities were improved by more than five-fold, while methoxy, bromo and fluoro substituents had only minor impacts on receptor binding. The most efficient ligands in the series, compounds 10 and 12, with K_i values of 1.9 and 0.97 nM, respectively, demonstrated >1000–fold selectivity over the the AT1 receptor and showed fair stability in human liver microsomes and human hepatocytes, but not in mouse liver microsomes. A tentative binding mode of inhibitor 12 was proposed after docking calculations.

The valorization of biomass into renewable, high-performance, adsorbent materials offers a sustainable alternative to conventional synthetic sorbents. In this study, we investigate the potential of lignin derivatives as efficient adsorbents for removing the cationic dye Rhodamine B (RhB) from aqueous solutions. Five organosolv lignin derivatives were synthesized via a one-step process using phenol, catechol, resorcinol, pyrogallol, and hydroquinone as phenolic modifiers to introduce structural diversity. The influence of these modifications on the materials’ physicochemical properties and adsorption behavior was examined. Comprehensive characterization included ³¹P NMR, Brunauer–Emmet–Teller surface area analysis, size exclusion chromatography, thermogravimetric analysis, and dynamic light scattering. Among the derivatives, resorcinol-modified lignin (ReL) showed the highest RhB adsorption capacity (101.2 mg g⁻¹), attributed to its favorable textural properties—high surface area and pore volume—together with increased availability of functional groups, which collectively enhanced adsorption efficiency. Adsorption kinetics for all materials followed the pseudo-second-order model, indicating chemisorption as the dominant mechanism. Isotherm analyses revealed Langmuir-type monolayer adsorption for ReL, pyrogallol-modified, and hydroquinone-modified lignins. Moreover, ReL demonstrated good recyclability, retaining 62% of its adsorption efficiency after five adsorption–desorption cycles. Collectively, these results highlight the promise of structurally engineered lignin-based adsorbents as cost-effective, efficient, and reusable materials for sustainable wastewater treatment.

Nonnatural amino acids are pivotal for expanding the functional diversity of peptides and proteins, enabling novel therapeutic opportunities. Mono-Boc-protected spirocyclization precursors have been developed as versatile intermediates for the diastereoselective synthesis of spirooxindole-based nonnatural amino acids by the Mizoroki-Heck reaction. Catalytic hydrogenation produced cyclopentyl derivatives, expanding the diversity of these amino acids. Furthermore, one spirooxindole derivative was incorporated into a tripeptide by solid-phase peptide synthesis on Rink amide resin to demonstrate its potential in peptide modification and drug development.

Small-molecule inhibitors of the zinc metalloprotease insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), are a promising newclass of potential cognitive enhancers for the treatment of neurodegenerative disorders such as Alzheimer's disease. Previous studies identifieda series of sulfonamide-substituted benzylhydroxamic acids with fair BBB permeability, no indication of efflux and subnanomolar potency. We herein report our further structural optimization of this compoundseries focusing on various alterations to the sulfonamide group. Notably, introduction of dihydropyridopyrimidine provided the most active small-molecule inhibitor compound reported to date, with an IC₅₀ valueof 34 nM. Molecular modeling studies, based on free energy perturbation simulations, show that the accommodation of the explored substit-uents on the binding mode proposed explain the experimental SARherein reported and provide a rationale for the enhanced affinity of theoptimized compounds.

This study explores the potential of phenolated lignin as a precursor for synthesizing graphene-like carbon materials through laser-induced carbonization (LIC). Key parameters─including formulation, laser speed, laser power, and lignin loading─were optimized to enhance the quality of the resulting LIC materials. Under optimized conditions, this method produced a high-quality, few-layer graphene-like carbon material. Comprehensive materials characterization (XPS, XRD, TGA, Raman spectroscopy, sheet resistivity, and elemental analysis) revealed that the material’s conductivity is driven by the formation of an sp2-hybridized conjugated carbon system and the reduction of both sp3-hybridized carbon and oxygen groups. The introduction of phenolic groups into the lignin structure enhanced its thermostability and conversion efficiency to graphene-like carbon, achieving a low sheet resistance of 6.7 Ω·sq–1. This study demonstrates that phenolated lignin is a promising precursor for the synthesis of conductive graphene-like carbon materials with excellent electronic properties, making it suitable for micro-supercapacitor applications. Furthermore, the resulting printed device exhibited a specific capacitance of 454 mF cm–3 (1.4 mF cm–2) at a scan rate of 5 mV s–1 in cyclic voltammetry (CV) mode and 286 mF cm–3 (0.86 mF cm–2) at a current density of 0.05 mA cm–2 in galvanostatic charge–discharge (GCD) mode.

Insulin-regulated aminopeptidase (IRAP) is emerging as a pharmaceutical target for treatment of neurotoxic- and neurodegenerative symptoms commonly seen in cognitive impairments. Ligands of IRAP, such as Angiotensin IV and similar analogues, bind to the active site of IRAP and causes an inhibition of its enzymatic activity, which is suggested to improve cognitive functions. Opioids are widely used in the clinic to treat for example pain and opioid use disorder, however opioid use have been associated with cognitive impairments, impaired neuronal development, and neuronal damage. To evaluate the potential of the macrocyclic IRAP inhibitor compound 9 (C9), the present study examined the restorative effects of C9 after opioid-induced cell toxicity. The toxic impact of the commonly used opioids methadone and buprenorphine was determined in rat primary hippocampal and cortical cells, along with the effects on various viability markers after subsequent treatment with C9. The metabolism of tetrazolium bromide salt (MTT) was measured to assess mitochondrial activity, and the level of membrane damage was assessed by measuring lactate dehydrogenase (LDH) in the cell media. Fluorescent calcein dye was used to evaluate intracellular esterase activity. In conclusion, this study demonstrate that methadone and buprenorphine induce toxic effects in primary hippocampal and cortical cell cultures and that IRAP inhibitor C9 has a restorative effect on intracellular esterase activity in methadone-damaged cells.