Search Results (204)

9-Mesitylacridinium salts are widely recognized as efficient organic photoredox catalysts owing to their strong excited-state oxidizing power and stability under visible-light irradiation. In this study, a new mesityl acridinium derivative bearing a di-tert-butylphenyl substituent on the nitrogen atom was synthesized. The introduction of tert-butyl groups on the N-aryl moiety was primarily aimed at improving solubility and chemical stability of the acridinium salt. Starting from a 9(10H)-acridinone precursor, the target compound was obtained in high overall yield through a concise synthetic sequence. The synthesis consists of a copper-catalyzed C–N coupling reaction to install the aryl substituent on the nitrogen atom, followed by a Grignard reaction and subsequent acid treatment to afford the corresponding acridinium salt. All transformations proceeded smoothly, providing efficient access to the desired novel acridinium derivative. This work presents a practical example of the structural modification of mesitylacridinium derivatives directed toward enhanced solubility and stability, and provides a useful synthetic platform for the preparation of structurally diverse acridinium salts. Full article

The photocycloaddition (PCA) of chalcones represents an important reaction pathway for accessing substituted cyclobutanes, which is a molecular framework with utility in synthetic chemistry, materials science, and medicine. In the past, our group has demonstrated the utility of the large cavity of γ-CD as a container for encapsulating two photo reactants for directing the PCA of several classes of aryl alkenes with high stereo- and regioselectivity: the cavitand-mediated photodimerization (CMP) approach. The CMP of chalcones reported in this work further demonstrates the effectiveness of this approach as high yields of dimers were observed in the photoreactions, while they were non-reactive in the solid state and yielded only the isomerization product in homogeneous media. The γ-CD CMP of chalcones yielded predominantly dimerized products in very good to high yields (>70%), composed of a mixture of three dimers in different proportions with syn HH as the major product. Computational analysis of the ground state complex structures revealed a strong correlation between the stability of the complex and predominance of the stereoisomer in the mixture. Further insights were deduced from temperature-dependence studies, which showed a shift in dimer selectivity tending towards a single stereoisomer. Full article

Background/Objectives: Thrombin, a serine protease central to coagulation and platelet activation, remains an important target for the development of safer and more effective antithrombotic agents. Naturally derived pentacyclic triterpenoids, such as betulinic acid and its acetylated derivatives, 3β-acetoxybetulinic acid, exhibit promising antiplatelet aggregation activity in validated in vitro and ex vivo assays; however, the molecular determinants underlying their direct thrombin inhibition remain unexplored. Results: Docking and MM/GBSA analyses revealed that Baa exhibits the strongest binding affinity (ΔG = −29.58 ± 2.97 kcal/mol), exceeding those of Ba (−20.94 ± 5.81 kcal/mol) and Asp (−18.87 ± 4.18 kcal/mol). Baa forms a highly persistent hydrogen bond with Trp96 (95.5% occupancy) and extensive hydrophobic contacts with Trp215, Leu99, Ile174, and Tyr60A residues defining thrombin’s aryl-binding pocket. MD trajectories demonstrated that Baa binding reduced solvent-accessible surface area (SASA) and residue fluctuations, indicating enhanced structural compaction and stability. In contrast, Ba exhibited weaker, transient hydrogen bonding, while Asp bound primarily near the catalytic triad. The triterpenes exhibit limited oral bioavailability, free PAINS alerts, favourable permeability and metabolic stability. Conclusions: Acetylation at C-3 (acetoxy substitution) substantially enhances thrombin binding via cooperative hydrogen bonding and van der Waals stabilisation, explaining the superior experimental inhibitory potency of Baa. These findings provide a mechanistic framework for structure-guided optimisation of triterpenoid-based thrombin inhibitors and support their further experimental development. Methods: In this study, molecular docking, molecular dynamics (MD) simulations (400 ns), and MM/GBSA free energy analyses were employed to elucidate the binding mechanisms of 3β-acetoxybetulinic acid (Baa), betulinic acid (Ba), and aspirin (Asp) within the thrombin receptor active site. The simulations were explicitly grounded in previously reported chromogenic antithrombin assays and platelet aggregation studies and were designed to mechanistically rationalise the experimentally observed inhibitory potency. Full article

Introduction: Uremic toxins have been shown to cause adverse pulmonary effects by inducing endothelial and epithelial dysfunction, disrupting the alveolar-capillary barrier, and increasing inflammation and oxidative stress. This article reviews these effects with a specific focus on chronic kidney disease and the mechanisms by which uremic toxins affect lung tissue. Methods: A narrative review was conducted using keywords related to uremic toxins and lung injury to search the PubMed database. An advanced literature review was conducted in PubMed to identify studies explaining the mechanisms underlying lung pathophysiology in chronic kidney disease (CKD), with particular focus on CKD-induced pulmonary epithelial and endothelial dysfunction. Additionally, to highlight the pathological processes of lung congestion in CKD, studies on CKD-induced dysfunction of the alveolar-capillary barrier were retrieved. Studies published up to November 2025 were evaluated. Results: A total of 148 articles were reviewed in full text. Uremic toxins negatively impact lung tissue structure and function through multiple mechanisms, including oxidative stress, inflammation, and direct effects. Uremic toxins appear to share signaling pathways in endothelial cells, including those linked to Mitogen-activated protein kinases (MAPK), the Aryl Hydrocarbon Receptor (AhR), the receptor for advanced glycation end products (RAGE), and pro-inflammatory transcription factors such as nuclear factor κB (NF-κB). Additionally, oxidative stress acts as a pro-inflammatory signal shared by several uremic toxins. The mechanisms behind the harmful interactions between CKD and lung disease are mostly unknown, although more evidence exists for acute kidney injury (AKI). Conclusions: Chronic kidney disease, which leads to the buildup of uremic toxins, negatively affects the lungs. Overall, the accumulation of uremic toxins in CKD impairs endothelial and epithelial cells and the alveolar capillary barrier. Further research is needed to understand the specific mechanisms underlying these effects and to identify therapeutic options to protect the lungs in these patients. Full article

Advanced chronic kidney disease (CKD) is associated with impaired humoral immunity, contributing to increased infection-related mortality and suboptimal vaccine responses, as notably observed during the COVID-19 pandemic. CKD is also marked by the accumulation of uremic toxins, but whether they directly influence T and B cell functionality remains unclear. In this translational study, we integrated clinical and biological data from 106 CKD patients with mechanistic insights from in vitro and in vivo murine models to identify the mechanisms underlying CKD-associated defects in humoral responses against T cell-dependent antigens. Contrary to our initial hypothesis, indoxyl sulfate—despite its known ability to activate Aryl hydrocarbon Receptor signaling in monocytes—did not directly impair T–B cell cooperation in coculture assays. Similarly, plasma levels of ten major uremic toxins showed no correlations with vaccine-induced antibody titers in patients. Instead, systemic inflammation emerged as the primary driver of defective humoral immunity. Murine models further confirmed that inflammation, rather than uremia alone, induces lymphopenia, disrupts lymphoid architecture, and ultimately impairs antibody production. These findings indicate that CKD-associated inflammation, rather than a direct effect of uremic toxins on adaptive immune effectors, underlies humoral immune dysfunction in CKD. Targeting inflammation may, therefore, offer a promising strategy to improve vaccine efficacy and reduce infection-related complications in this vulnerable population. Full article

The family Arenaviridae encompasses zoonotic, rodent-borne pathogens (e.g., Lassa, Machupo, and Junín viruses) that cause severe viral hemorrhagic fevers with high case fatality rates. The current therapeutic landscape is severely limited, underscoring the urgent need for novel antiviral strategies. A promising approach involves combining directly acting antivirals with host-targeted antivirals. A compelling host-targeted antiviral target is the aryl hydrocarbon receptor (AHR). This ubiquitous ligand-activated transcription factor is a recognized pro-viral host factor across multiple viral families. Building on prior work with Junín and Tacaribe viruses, we investigated whether the AHR inhibitor CH223191 could enhance the virus-directed antiviral activity of favipiravir against these viruses. First, we evaluated the toxicity and antiviral potential of CH223191 against a lethal Junín virus infection in male and female hTfR1 mice. After demonstrating substantial protection, we conducted preliminary assays to study the antiviral effects of combining CH223191 and favipiravir on Tacaribe virus (TCRV) infections in the Vero cell culture model. We observed synergistic interaction with all four models (ZIP, Loewe, Bliss, and HSA). We next determined the sub-optimal dose of favipiravir and conducted an antiviral combination study in the AG129 mouse model infected with TCRV. The combination effectively protected mice from a lethal TCRV infection and showed cooperative effects, reducing weight loss and viral loads. Overall, these results show that the AHR is a promising pharmacological target for the development of novel antivirals. Furthermore, we discovered a cooperative interaction between the activities of favipiravir and CH223191. Full article

Background: Among the 15 human (h) carbonic anhydrase (CA; EC 4.2.1.1) isoforms, hCA IX and XII are particularly important due to their roles in tumor cell growth and survival, identifying them as promising targets for anticancer therapy. As a result, considerable effort has been directed toward the development of novel inhibitors that are highly selective for these isoforms. Methods: A library of twelve novel N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carbothioamides 3 along with two new N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carboxamide derivatives 5 were synthesized and their inhibition abilities were tested against four human carbonic anhydrase isozymes (hCA I, II, IX and XII) related to some global diseases including glaucoma, cancer and osteoporosis. Results: All compounds exhibited potent inhibition of the tested isoforms in the nanomolar range. Compound 3i showed the highest inhibition of hCA I activity but demonstrated poor selectivity toward the other isoforms. Compound 3h displayed superior selectivity for hCA II over hCA I (hCA I/II = 37) and exhibited 2.5-fold higher inhibitory activity compared to acetazolamide (AAZ). Among the tested compounds, 3l (K_i = 32.1 nM) demonstrated markedly improved selectivity for hCA IX over hCA I, II, and XII relative to the standard drug. Notably, compound 3a showed the most potent inhibition against hCA XII (K_i = 6.8 nM), comparable to AAZ, while exhibiting significantly greater selectivity over off-target isoforms and the other tumor-associated isozyme (hCA IX/XII = 20 versus hCA IX/XII = 4.5 for AAZ). Conclusions: The present study suggests potent lead compounds as selective hCA IX and XII inhibitors with anticancer activity. Full article

Syringic acid (SA) is a natural derivative of syringaldehyde (SD), derived from lignin depolymerization. Its application in the food industry focuses on the properties of natural functional ingredients; it is mainly used as a food antioxidant and food preservative, but can also be used as an ingredient to enhance food flavor and functional foods. This compound exhibits a remarkable spectrum of biological activities, including potent antioxidant, anti-inflammatory, neuroprotective, hypoglycemic, detoxifying, and anti-cancer effects, positioning it as a highly promising candidate for pharmaceutical and nutraceutical applications. In this study, suitable sites were first screened through homologous sequence alignment, and a variant of aryl-alcohol oxidase (CgAAO) with high efficiency in catalyzing the conversion of SD to SA was obtained via site-directed mutagenesis. A deep eutectic solvent (DES) system based on choline chloride/urea (ChCl/UR) in water was developed to enhance SA production. Additionally, key parameters of the biological reaction were optimized, including temperature, pH, metal ions, as well as the type and dosage of DES. The optimal performance was achieved using recombinant E. coli pRSFDuet-CgAAO-Y335F whole-cell biocatalysts, yielding 75% and producing 0.75 g/L SA in 100 mM KPB buffer (pH 7.0) containing 5 wt% ChCl/UR and 1 mM Fe³⁺. This study established a novel biosynthetic pathway for SA that was efficient, mild, green, and environmentally friendly. Full article

Environmental allergens trigger epithelial reactive oxygen species (ROS) production and cellular senescence, contributing to airway inflammation. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor responsive to environmental stimuli, may modulate this process. Single-cell transcriptomics from allergen-challenged bronchoalveolar brushings of allergic asthma and non-asthmatic allergic control subjects were analyzed for ROS, senescence, and AhR activity. Club cell-specific p16 knockout (p16^ΔScgb1a1) and AhR-deficient (AhR^ΔScgb1a1) mice were used to assess epithelial senescence and AhR function. Single-cell analysis revealed epithelial senescence as a hallmark of allergen-induced asthma. p16^ΔScgb1a1 mice exhibited reduced ROS levels and airway inflammation. Single-cell analysis also demonstrated increased AhR activity and ROS generation in airway epithelial cells of allergen-treated asthmatics, and ROS correlated positively with AhR activity and senescence. It was documented that the regulation of AhR on senescence was attenuated by VAF347, whereas AhR deficiency exacerbated ROS generation and inflammation in AhR^ΔScgb1a1 mice. RNA-seq identified senescence as a key AhR-regulated pathway, implicating c-Myc, TGF-β2, and SERPINE1 as major targets. AhR binding to the c-Myc promoter was confirmed by ChIP-PCR, and pharmacologic inhibition of c-Myc with EN4 reduced allergen-induced ROS, senescence, and inflammation. These findings demonstrate that epithelial AhR suppresses allergen-induced ROS generation and cellular senescence via direct regulation of c-Myc. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with immune dysregulation, skin barrier dysfunction, and microbial dysbiosis characterized by Staphylococcus aureus overcolonization and reduced bacterial diversity. Beyond its classical role in calcium homeostasis, Vitamin D (VD) influences skin immunity and microbial composition. This review summarizes current knowledge on VD metabolism, its immunological pathways in AD, and its interactions with the skin microbiome. Recent evidence positions the skin as an active immunological organ rather than a passive barrier. Commensal bacteria such as Staphylococcus epidermidis not only inhibit pathogens by producing bacteriocins and modulins but also generate ceramides and short-chain fatty acids (SCFAs) that stabilize the lipid barrier. Moreover, dermal fibroblasts and preadipocytes produce antimicrobial peptides, while resident γδ T cells release growth factors like fibroblast growth factor 7 (FGF7), linking host defense with tissue regeneration. VD modulates AD by suppressing T helper 2 cells/T helper 17 cell responses, enhancing regulatory T cell development, inducing antimicrobial peptides, and strengthening skin and gut barrier integrity. Its interaction with the microbiome and pathways such as SCFA and aryl hydrocarbon receptor (AhR) signaling supports its potential as an adjunctive therapy in AD management. Evidence from mechanistic studies and animal models suggests that VD supplementation may modulate inflammation and microbial diversity. Clinical implications, therapeutic perspectives, and future research directions highlight the potential of VD as a therapeutic adjunct in AD management. Full article

β-Lactams are key scaffolds in synthetic and medicinal chemistry, valued for both therapeutic relevance and synthetic utility. Classical ketene-imine [2+2] cycloadditions often employ stabilized aryl ketenes, which display reduced reactivity and modest stereoselective. Disruption of π-conjugation in N-pyrrolylketene has been shown to enhance electrophilicity and direct stereochemical outcomes in reactions with aromatic imines. The ketene, generated in situ from N-pyrrolylpropanoic acid, undergoes cycloaddition under mild conditions to give β-lactams with a strong preference for the trans isomer. Frontier molecular orbital analysis and mechanistic interpretation suggest a polar asynchronous pathway, highlighting ketene destabilization as a practical strategy for stereoselective β-lactam synthesis. Full article

Background/Objectives: COVID-19 was responsible for millions of deaths worldwide. This study aimed to identify substances with in vitro and in vivo effects against the SARS-CoV-2 virus. Methods: Compounds PQM-243 and PQM-249, two terpene-N-acyl-aryl-hydrazone analogues, were evaluated in vitro against SARS-CoV-2 to a antiviral activity and inhibitory effect against angiotensin converting enzyme 2 (ACE2). A possible inhibitory effect affecting the interaction between the receptor-binding domain (RBD) protein and/or ACE2 was evaluated using LUMMIT kit. A SARS-CoV-2-induced pulmonary pneumonia model was developed to evaluate the effects of the compounds after 3 days of treatment. Results: Compounds PQM-243 and PQM-249 exhibited IC₅₀ values of 0.0648 ± 0.041 µM and 0.2860 ± 0.057 µM against SARS-CoV-2 with a selective index of >1543.21 and 349.65, respectively, and IC₅₀ values of 12.1 nM and 13.3 nM, respectively, against ACE2. All concentrations used significantly reduced interactions between ACE2 and RBD. Computational studies suggest that these new compounds are potent direct anti-SARS-CoV-2 agents, capable of reducing both virus viability and its invasive ability in the host cells by reducing the interaction between RBD and ACE2. It was also demonstrated that even when administered by the oral route, both compounds reduced SARS-CoV-2-induced lung inflammation. Our data suggests that both compounds can act as potent direct anti-SARS-CoV-2 agents, reducing both viral viability and host cell entry. In addition, they exhibited a significant multi-target-directed pharmacological profile, also reducing SARS-CoV-2-induced lung inflammation when administered orally. Conclusions: Overall, these findings support further investigation of PQM-243 and PQM-249 as promising antiviral and anti-inflammatory multi-target prototypes for the development of innovative drug candidates targeting SARS-CoV-2 and other virus-related respiratory diseases. Full article

Perfluorooctane sulfonamide (PFOSA), the direct precursor to perfluorooctane sulfonate (PFOS), is widely present in the environment. Research has indicated that PFOSA is cardiotoxic and hepatotoxic, but its impact on neurodevelopment remains unclear. In the current study, we observed that exposure of PFOSA caused neurodevelopmental toxicity in zebrafish embryos in a dose-dependent manner, as evidenced by impaired motor abilities and decreased swimming distance. We then demonstrated that PFOSA exposure downregulated the mRNA expression of neurodevelopment-related genes including a1-tubulin, elavl3, ache and dat. Moreover, PFOSA exposure resulted in dose-dependent oxidative stress, which triggers apoptosis in the brains of zebrafish larvae. We further showed that inhibition of the aryl hydrocarbon receptor (AhR) alleviated the oxidative stress and apoptosis induced by PFOSA, thereby counteracting the neurodevelopmental abnormalities in zebrafish larvae. In conclusion, these findings indicate PFOSA causes neurodevelopmental disorders by inducing oxidative stress and apoptosis through the AhR pathway. Full article

Treatment of N,N-dimethylhydrazinoalkenes with diethylzinc followed by exposure of the resulting ethylzinc amides to high vacuum drives a Schlenck redistribution metalloamination/cyclization to generate the corresponding bis(organozinc) intermediates in excellent conversions. Direct treatment of these with appropriate aryl or vinyl electrophiles in the presence of catalytic PdCl₂ (DPEphos) provides the corresponding arylated or alkenylated pyrrolidines and piperidines with high efficiency. Full article

As a model compound for lignin derivatives, anisole and its conversion are crucial for the upgrading of biomass resources. Anisole molecule contains a characteristic aryl ether bond (C_aryl-O-CH₃); therefore, the selective cleavage of the C-O bond to efficiently produce high-value chemicals poses a significant challenge. Constructing bimetallic synergistic active sites through tuning the metal-support interface is considered an effective strategy. In this work, the WO₃-promoted Pt/SiO₂ catalysts were investigated to enhance the performance of anisole hydrodeoxygenation (HDO) to hydrocarbons. Experimental results demonstrate that WO₃ significantly promotes HDO selectivity, increasing from 37.8% to 86.8% at 250 °C. Moreover, moderate doping improves low-temperature (<250 °C) HDO activity, confirming the presence of synergistic effects. In contrast, excessive WO₃ suppresses anisole conversion. Characterization results reveal that WO₃ stabilizes metallic Pt and facilitates H₂ dissociation. Concurrently, strong hydrogen spillover between Pt and WO₃ promotes oxygen vacancy formation on WO₃. This transforms disordered adsorption of anisole on SiO₂ into directed adsorption of the anisole’s oxygen species onto WO₃. This work achieves high anisole HDO selectivity through the Pt-WO₃ interface tuning, offering novel insights for efficient lignin conversion. Full article