Search Results (562)

Background/Objectives: Ligands blocking σ₁ receptors or NMDA receptors show promising pharmacological properties, such as analgesia or neuroprotection. It had been shown that depending on the stereochemistry and substitution pattern, 1,3-dioxnaes can selectively interact with either σ₁ receptors or the phencyclidine binding site of NMDA receptors. Herein, systematic modifications of homologous aminobutyl substituted 1,3-dioxanes were conducted in order to identify ligands selectively addressing σ receptors or NMDA receptors. Methods: The first step of the synthesis, i.e., the acetalization of benzaldehyde (7a) or propiophenone (7b) with pentane-1,3,5-triol (6), determined the relative configuration of the envisaged 1,3-dioxanes bearing 4-aminobutyl substituents in 4-position. Multi-step homologation of ethanols 8 provided various primary, secondary and tertiary amines 14, 16–19, and 24–27. The affinity towards σ₁ and σ₂ receptors as well as the PCP and ifenprodil binding sites of the NMDA receptor was systematically evaluated in radioligand receptor binding studies. Results: Only the primary amines 14b and 24b derived from propiophenone interacted moderately with the PCP binding site of the NMDA receptor. Within this class of compounds, the N-benzylamines 17 and 18 showed the highest σ₁ affinity with high selectivity over the PCP binding site and at least preference over the σ₂ receptor. The benzylamine 17a (K_i(σ₁) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (K_i(σ₁) = 154 nM, LLE = 6.72) represent the most promising σ₁ ligands of this compound series, when taking the lipophilicity and receptor selectivity into account. Conclusions: Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies. Full article

Inspired by naturally occurring bis-isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type bis-1-arylisochromans containing a stereogenic ortho-trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5′-linked heterodimeric bis-isochromans containing both central and axial chirality elements by performing diastereoselective Suzuki–Miyaura biaryl coupling reactions on two optically active 1-arylpropan-2-ol derivatives, followed by two oxa-Pictet–Spengler cyclizations with aryl aldehydes or methoxymethyl chloride. We studied the diastereoselectivity of the cyclization step, separated the stereoisomeric products with chiral preparative HPLC and determined the absolute configuration through a combination of vibrational circular dichroism (VCD), NMR and single-crystal X-ray diffraction analysis. We demonstrated that different aryl groups could be introduced into the two isochroman subunits, since the dimethoxyaryl subunit reacted faster, enabling the two oxa-Pictet–Spengler cyclizations to be performed separately with different aryl aldehydes. We also explored the acid-catalyzed isomerization and oxidation to axially chiral ortho-quinones in order to produce stereoisomeric and oxidized analogs, respectively. We identified the antibacterial activity of our target bis-isochromans against Bacillus subtilis and Enterococcus faecalis with minimum inhibitory concentrations down to 4.0 and 0.5 μg/mL, respectively, which depend on the stereochemistry and substitution pattern of the bis-isochroman skeleton. Full article

While omega-6 fatty acids play an important role in normal cell function, their excess in the diet is associated with an increased risk of developing diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and Alzheimer’s disease. Furthermore, excessive intake has been shown to lead to chronic inflammation, which is related to increased production of reactive oxygen species (ROS). This conditioncan initiate lipid peroxidation in cell membranes, leading to the degradation of their fatty acids. One of the main products of omega-6 peroxidation is the α,β-unsaturated aldehyde, i.e., 4-hydroxynonenal (4-HNE), which is able to form four diastereoisomeric adducts with guanine. These 4-HNE adducts have been identified in the DNA of humans and rodents. Depending on their stereochemistry, they are able to influence double helix stability and cause DNA–DNA or DNA–Protein cross-links. Moreover, studies have shown that 4-HNE adducts formed in the human genome are considered mutation hotspots in hepatocellular carcinoma. Although the cell possesses defence mechanisms, without a well-balanced diet allowing correct cell function, they may not be sufficient to protect the genetic code. This review provides an overview of the molecular mechanisms underlying oxidative stress, lipid peroxidation, and the formation of DNA adducts. Particular emphasis is placed on the role of an omega-6-rich diet in inflammatory diseases, and on the formation of 4-HNE, which is a major product of lipid peroxidation, and its broader implications for genome stability, ageing, and disease progression. Full article

Accurate prediction of drug–drug interactions (DDIs) is essential for ensuring medication safety and optimizing combination-therapy strategies. However, existing DDI models face limitations in handling interactions related to stereochemistry and precisely locating drug interaction sites. These limitations reduce the prediction accuracy for conformation-dependent interactions and the interpretability of molecular mechanisms, potentially posing risks to clinical safety. To address these challenges, we introduce LSA-DDI, a Spatial-Contrastive-Attention-Based Drug–Drug Interaction framework. Our 3D feature extraction method captures the spatial structure of molecules through three features—coordinates, distances, and angles—and fuses them to enhance the model of molecular spatial structures. Concurrently, we design and implement a Dynamic Feature Exchange (DFE) mechanism that dynamically regulates the flow of information across modalities via an attention mechanism, achieving bidirectional enhancement and semantic alignment of 2D topological and 3D spatial structure features. Additionally, we incorporate a dynamic temperature-regulated multiscale contrastive learning framework that effectively aligns multiscale features and enhances the model’s generalizability. Experiments conducted on public drug databases under both warm-start and cold-start scenarios demonstrated that LSA-DDI achieved competitive performance, with consistent improvements over existing methods. Full article

The bis-thiourea chiral solvating agent (CSA) BTDA enables the NMR-based determination of absolute configuration in N-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both ¹H and ¹³C NMR spectra. A dual-enantiomer approach, using (R,R)- and (S,S)-BTDA, generates diastereomeric complexes with the enantiopure substrate, and distinct spatial arrangements are reflected in consistent and interpretable Δδ values. The observed chemical shift differences correlate reliably with the stereochemistry of the chiral center and are further supported by ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) experiments and binding constants’ measurements, confirming the formation of stereoselective non-covalent complexes. This methodology extends the logic of Mosher’s analysis to solvating agents and remains effective even in samples containing single pure enantiomers of the amino acid derivative. The BTDA-based dual-CSA system thus represents a robust, non-derivatizing strategy for stereochemical assignment by NMR, combining operational simplicity with broad applicability to DNB derivatives of amino acids with free carboxyl function. Full article

Kynurenic acid (KYNA) derivatives condensed with an aromatic ring (tricyclic KYNA derivatives) have been successfully synthesized, and the reactivity of these analogues has been investigated in the modified Mannich reaction resulting in new Mannich bases. The N,N-dimethyl-ethylenediamine analogues of the tricyclic KYNA derivatives have also been successfully synthesized, and their reactivity in the modified Mannich reaction was investigated. The synthesized ring systems bear resemblance to molecules previously investigated as G-quadruplex binding agents. Based on this similarity, the synthesized tricyclic KYNA derivatives could be investigated as potential antiviral and anticancer molecules. Full article

Kynurenic acid (KYNA), a putative neuroprotective agent, modulates glutamatergic pathways in schizophrenia and Parkinson’s disease but is limited by acute motor activity impairments (e.g., ataxia). Research leveraging animal disease models explores its structure–activity relationship to enhance therapeutic efficacy while mitigating adverse effects, addressing global neuropsychiatric disorders affecting over 1 billion people. Structural analogs of KYNA (SZR-72, SZR-73, and SZR-81) were designed to uncouple therapeutic benefits from motor toxicity; yet, systematic comparisons of their acute behavioral profiles remain unexplored. Here, we assess the motor safety, time-dependent effects, and therapeutic potential of these analogs in mice. Using acute intracerebroventricular dosing, we evaluated motor coordination (rotarod), locomotor activity (open-field), and stereotypic behaviors. KYNA induced significant ataxia and stereotypic behaviors at 15 min, resolving by 45 min. In contrast, all analogs avoided acute motor deficits, with SZR-73 maintaining baseline rotarod performance and eliciting a delayed decrease in ambulation and inquisitiveness in open-field assays. These findings demonstrate that the structural optimization of KYNA successfully mitigates motor toxicity while retaining neuromodulatory activity. Here, we show that SZR-73 emerges as a lead candidate, combining transient therapeutic effects with preserved motor coordination. This study advances the development of safer neuroactive compounds, bridging a critical gap between preclinical innovation and clinical translation. Future work must validate chronic efficacy, disease relevance, and mechanistic targets to harness the full potential of KYNA analogs in treating complex neuropsychiatric disorders. Full article

Sucrose is by far the most abundant disaccharide found in nature, consisting of two simple hexose units: d-glucose and d-fructose. This exceptionally inexpensive and widely accessible raw material is produced in virtually limitless quantities. The vast majority is consumed in the food industry either in its native form—as commercial table sugar—or, to a lesser extent, as the basis for artificial sweeteners such as palatinose and sucralose. Beyond its dietary use, sucrose serves as a feedstock for the production of bioethanol, liquid crystals, biodegradable surfactants, and polymers. However, the application of this valuable and extremely cheap raw material (100% optical purity and eight stereogenic centers with precisely defined stereochemistry) in the synthesis of more sophisticated products remains surprisingly limited. In this short review, we focus on the strategic use of the sucrose scaffold in the design and synthesis of fine chemicals. Special attention will be paid to macrocyclic derivatives incorporating the sucrose backbone. These water-soluble structures show promise as molecular receptors within biological environments, offering unique advantages in terms of solubility, biocompatibility, and stereochemical precision. Full article

Background/Objective: Avapritinib is an orally bioavailable tyrosine kinase inhibitor and was approved by the FDA in 2020 for gastrointestinal stromal tumor treatments. Although avapritinib is known to be chiral, its stereochemistry was initially established randomly. This study aims to develop a definitive method for determining avapritinib’s absolute configuration and propose a universal methodology for stereochemical characterization of flexible chiral drugs. Methods: The absolute configuration of avapritinib was determined through an integrated approach combining chiral resolution, chiroptical spectroscopy and synthetic validation. Enantiomeric separation was achieved via chiral liquid chromatography, followed by comprehensive chiroptical characterization including electronic circular dichroism (ECD), specific optical rotation and optical rotatory dispersion. Conformational analysis and density functional theory (DFT) calculations correlated experimental spectra with theoretical predictions, facilitating definitive configurational assignment. The stereochemical determination were further verified through ECD derivatization and chemical synthesis. Finally, the enantiomers’ kinase inhibition profiles against c-KIT D816V were quantitatively assessed. Results: Two enantiomers of avapritinib were resolved via chiral HPLC and a Chiralpak IG column. Through combined experimental ECD spectra and time-dependent DFT calculations employing the core extraction method, the levo-isomer was unambiguously determined as S configuration. This stereochemical assignment was confirmed by p-cyanobenzaldehyde derivatization and de novo synthesis. Biological evaluation revealed (S)-(−)-avapritinib exhibited superior c-KIT D816V inhibitory activity compared to its (R)-(+)-counterpart, a finding corroborated by molecular docking studies elucidating their differential target interactions. Conclusions: This study advances avapritinib stereochemical understanding and establishes a definitive protocol for its absolute configuration assignment, serving as a paradigm for flexible chiral drug characterization. Full article

The phenomena of regio- and stereoselectivity and the molecular mechanism of the [2 + 2] cycloaddition reaction between (E)-2-arylnitroethenes and the ynamine molecular system were analyzed using wb97xd/6-311 + G(d) (PCM) quantumchemical calculations. It was found that, independently of the stepwise nature of the cycloaddition, the full retention of the stereoconfiguration of the nitroalkene can be interpreted and explained. Next, the analysis of the electronic properties of the localized reaction intermediate suggests its possible zwitterionic nature. Additionally, the solvent and the substituent effect on the reaction course were also evaluated. In consequence, the proposed mechanism can be treated as general for some groups of [2 + 2] cycloaddition processes. Lastly, for the model process, the full Bonding Evolution Theory (BET) analysis along the reaction coordinate was performed. It was found that the [2 + 2] cycloaddition reaction between (E)-2-phenylonitroethene and ynamine begins with the formation of two pseudoradical centers at the C2 and C3 atoms. First, a C2-C3 single bond is formed in phase V by combining two pseudoradical centers, while the formation of a second C4-C1 single bond begins at the last, eleventh phase of the reaction path. A BET analysis of intermediate (I) allows it to be classified as a compound with a pseudoradical structure. Next to zwitterions and biradicals, it is evidently new type of intermediate on the path of the [2 + 2] cycloaddition reaction. Full article

Three new naphthalene–chroman dimer derivatives, daldinaphchromes A–C (1–3), two new chroman derivatives, daldichromes A (5) and B (6), along with five known compounds (4, 7–10) were isolated from the mangrove-derived fungus Daldinia eschscholzii HJX1P2. Their structures and stereochemistries were elucidated through detailed NMR and MS analyses, calculated electronic circular dichroism, and comparison with previously reported data. Compound 1 demonstrated inhibitory effects on nitric oxide (NO) production in LPS-induced RAW 264.7 cells, with an IC₅₀ value of 62.9 µM, and more effectively suppressed the expression of interleukin (IL)-6 than dexamethasone. A further mechanistic study suggested that 1 could prohibit the expression of iNOS in RAW 264.7 cells, and the molecular docking study suggested a possible interaction between 1 and the iNOS protein. Compounds 7 and 8 exhibited moderate to potent DPPH radical scavenging activity, with IC₅₀ values of 117.4 and 46.2 µM, respectively, compared with the positive control ascorbic acid (IC₅₀ = 45.6 µM). Compounds 4 and 10 showed ABTS⁺ radical scavenging activity, with IC₅₀ values of 66.6 and 33.2 µM, respectively, which were equal to or lower than that of the positive control vitamin C (IC₅₀ = 59.7 µM). Compounds 1–3, 7, and 9 showed antibacterial activity against three Staphylococcus aureus strains, with MIC values of 74.4–390.6 μM. Full article

The Bacillus horneckiae-like strain 2011SOCCUF3 was isolated from the marine sponge Spongia officinalis and its metabolome was studied for secondary metabolites with antimicrobial activity. Culturing in the presence of Diaion HP-20 resin and purifying the culture extract identified cyclo-phenylalanine-proline (cyclo-(Phe-Pro)), a 2,5-diketopiperazine (2,5-DKP), isolated as a major metabolite. Further, LCMS analysis of the extract showed the presence of two isomers of the molecule in the culture broth. To confirm the stereochemistry of the isomers observed in the natural extract, all four stereoisomers of cyclo-(Phe-Pro) were synthesised. NMR and LCMS studies identified the presence of both cis- and trans-cyclo-(Phe-Pro) isomers. Stability and epimerisation studies on synthetic isomers and the effect of culturing conditions suggested that the less stable cis isomer was naturally produced, which epimerised in culture broth. Full article

A stereoselective and scalable strategy for the synthesis of phosphorus-containing bicyclic and tricyclic compounds from 1-phenylphosphin-2-en-4-one 1-oxide is presented. This activated dienophile, available in both racemic and enantiopure forms, undergoes smooth [4+2] cycloadditions with acyclic and cyclic dienes, affording products with excellent yields and controlled stereochemistry. Notably, the cis/trans-fusion of the cycloadducts (phosphadecalones and phosphahexahydrochrysene) can be selectively controlled by fine-tuning the conditions of microwave-assisted cycloaddition reaction. The influence of temperature, time, and steric effects on cis/trans and endo/exo selectivity was examined in detail. The molecular structure, including the absolute configuration, of eight products has been determined by X-ray crystallography. These analyses further established the endo-selective nature of the cycloaddition, favoring the P=O face of the dienophile. Post-cycloaddition transformations of selected P-stereogenic phosphadecalone, such as isomerization, reduction and deoxygenation, demonstrate the synthetic versatility of the resulting products. Full article

A library of neoisopulegol-based amino and thiol adducts was developed from (+)-neoisopulegol, derived from commercially available (−)-isopulegol. Michael addition of different nucleophiles towards its highly active α,β-unsaturated γ-lactone motif was accomplished, resulting in diverse amino and thiol analogs in stereoselective reactions. Then, the lactone ring was opened, with NH₃ and benzylamine furnishing primary amide and N-benzyl-substituted amide derivatives, respectively. The in vitro antimicrobial effect of prepared compounds was also explored. The results revealed that naphthylmethyl-substituted β-aminolactone, the most promising compound, displayed selective inhibition for the Gram-positive bacteria S. aureus with an MIC (minimum inhibitory concentration) value of 12.5 μM. A docking study was performed to interpret the obtained results. Full article

Copper-thiolate nanostructures, formed through the self-assembly of cysteine (Cys) and glutathione (GSH) with copper ions, offer a versatile platform for redox-active applications due to their structural stability and chemical functionality. In this study, Cu-Cys-GSH nanoparticles were synthesized and employed to develop a capacitive biosensor for the ultralow concentration detection of hydrogen peroxide (H₂O₂). The detection mechanism leverages a Fenton-like reaction, where H₂O₂ interacts with Cu-Cys-GSH nanoparticles to generate hydroxyl radicals (·OH) through redox cycling between Cu²⁺ and Cu⁺ ions. These redox processes induce changes in the sensor’s surface charge and dielectric properties, enabling highly sensitive capacitive sensing at gold interdigitated electrodes (IDEs). The influence of chirality on sensing performance was investigated by synthesizing nanoparticles with both L- and D-cysteine enantiomers. Comparative analysis revealed that the stereochemistry of cysteine impacts the catalytic activity and sensor response, with Cu-L-Cys-GSH nanoparticles exhibiting superior performance. Specifically, the biosensor achieved a linear detection range from 1.0 fM to 1.0 pM and demonstrated an ultra-sensitive detection limit of 21.8 aM, outperforming many existing methods for H₂O₂ detection. The sensor’s practical performance was further validated using milk and saliva samples, yielding high recovery rates and confirming its robustness and accuracy for real-world applications. This study offers a disposable, low-cost sensing platform compatible with sustainable healthcare practices and facilitates easy integration into point-of-care diagnostic systems. Full article