Anti-inflammatory & anti-allergy agents in medicinal chemistry最新文献

Introduction: The historical discovery that thrombin activates Protease-Activated Receptor 4 (PAR4) has paved the way for several novel findings. Besides thrombin, the complement lectin pathway protease Mannose-Binding Lectin-Associated Serine Protease-1 (MASP-1) also binds to PAR4, albeit with lower affinity. Similar to thrombin, MASP-1 activates Ca²⁺ signaling pathways in endothelial cells. MASP-2, a homolog of MASP-1, plays an important role in complement activation; however, its direct interaction with PAR4 has not yet been elucidated. In this study, we performed structural investigations of thrombin, MASP-1, and MASP-2 to evaluate their binding affinities toward the PAR4 peptide.

Methods: We employed in silico docking, binding affinity calculations, molecular dynamics simulations, and mutagenesis studies to test our hypothesis.

Results: For the first time, we demonstrate that, like thrombin and MASP-1, MASP-2 binds to PAR4 with appreciable affinity and could serve as a potential agonist of the PAR4 receptor and its associated inflammatory signaling pathways.

Discussion: The high sequence similarity of MASP-2 with MASP-1 and thrombin is an important factor in attaining comparable binding with the PAR4 peptide.

Conclusion: Our findings may pave the way for future investigations into the signaling mechanisms and therapeutic potential of PAR4-mediated inflammatory diseases.

Introduction: Phenothiazine derivatives represent an important class of heterocyclic compounds known for a wide range of pharmacological activities. Their antioxidant potential has drawn considerable interest for therapeutic applications against oxidative stress-related disorders. This study focused on synthesizing a new series of phenothiazine derivatives and evaluating their antioxidant activity.

Methods: A series of phenothiazine derivatives [5a-5h] was synthesized by conjugating phenothiazine with various aryl amines via an acetyl linker using standard organic synthesis techniques. The structures of the synthesized compounds were confirmed using spectroscopic techniques, including FT-IR, ^1H NMR, ^13C NMR, and mass spectrometry (MS). Antioxidant activity was assessed using two in vitro assays: the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method and the low-density lipoprotein (LDL) oxidation inhibition assay.

Results: All synthesized compounds were successfully characterized by the aforementioned spectroscopic techniques. The antioxidant assays revealed that most of the derivatives exhibited notable antioxidant activity. Among them, Compound 5e, bearing a 4-amino-2-methoxyphenol moiety, demonstrated the highest activity, surpassing the standard antioxidants Vitamin C and butylated hydroxyanisole (BHA). Conversely, compound 5h showed comparatively lower activity.

Discussion: The findings indicate that structural variations, particularly the presence of electrondonating groups on the phenothiazine ring, significantly influence antioxidant potential. The superior performance of Compound 5e highlights the importance of specific substituent patterns in enhancing biological activity. However, further investigation into pharmacokinetics and in vivo efficacy is necessary to support potential therapeutic use.

Conclusion: The study successfully synthesized and characterized a novel series of phenothiazine derivatives, several of which exhibited potent antioxidant properties. Structure- activity relationship (SAR) analysis suggested that electron-donating substituents enhance activity, pointing to promising future applications in treating oxidative stress-related conditions.

This review summarizes recent advances in ligand trap therapies targeting activin type II receptors [ActRIIA/ACVR2A and ActRIIB/ACVR2B], which serve as shared receptors for members of the TGF-β family, including activins, GDF11, and myostatin [MSTN]. These receptors mediate Smad2/3 signaling and play critical roles in hematopoiesis, vascular homeostasis, and muscle regulation. Two peptide-based ligand traps have recently received clinical approval: luspatercept [ActRIIB-Fc], an erythroid maturation agent, and sotatercept [ActRIIA-Fc], a novel therapeutic agent for pulmonary arterial hypertension [PAH]. Luspatercept primarily inhibits activin B and GDF11, thereby promoting late-stage erythropoiesis and demonstrating efficacy in anemia associated with conditions such as myelodysplastic syndromes [MDS] and β-thalassemia. Sotatercept binds activins and GDFs to rebalance Smad2/3 and Smad1/5/8 signaling, thereby improving vascular remodeling in PAH. Although both agents have failed to increase skeletal muscle mass in clinical trials consistently, they represent significant advances in the treatment of hematopoietic and vascular disorders. Future studies should focus on optimal dosing strategies, long-term safety, and potential synergistic effects when combined with other therapeutic modalities.

Osteoarthritis (OA) is a common, chronic degenerative joint disease that leads to the progressive degeneration of articular cartilage, subchondral bone, and synovium. In short, it is characterized primarily by inflammation, cartilage breakdown, and subchondral bone remodeling leading to joint pain, stiffness, and severe functional limitations. OA pathogenesis results from complex reciprocal interactions between genetic, mechanical, and environmental factors that culminate in the activation of pro-inflammatory mediators such as Interleukin 1β (IL 1β) and Tumor Necrosis Factor alpha (TNF α), which stimulate Matrix Metalloproteinases (MMPs) and break down the cartilage extracellular matrix. Additionally, oxidative stress, mitochondrial dysfunction, and chondrocyte senescence play crucial roles in disease progression. Consequently, adipokines have become important contributors to OA pathophysiology, with special emphasis on visfatin. These molecules released from adipose tissue also represent a systemic proinflammatory signal, found at higher concentrations in OA synovial fluid, and contribute to cartilage degradation and worsening of clinical symptoms. Visfatin participates in various signaling pathways to further amplify inflammatory cascades and cartilage destruction. In this review, we explore the role of visfatin and its possible mechanisms contributing to the progression of OA.

Microsponge drug delivery systems represent an innovative approach to enhancing the therapeutic efficacy of anti-inflammatory drugs through controlled release, improved bioavailability, and targeted delivery. These porous polymeric microspheres, ranging from 5 to 300 μm, encapsulate active pharmaceutical ingredients (APIs) to achieve sustained drug release, minimizing systemic side effects and dosing frequency. Chronic inflammatory conditions, such as rheumatoid arthritis, inflammatory bowel disease (IBD), and psoriasis, often require prolonged treatment, but conventional therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are limited by systemic toxicity and frequent administration. Microsponges address these challenges by enhancing drug stability, increasing retention at the target site, and reducing systemic exposure. Advanced fabrication techniques, including emulsion solvent diffusion, liquid-liquid suspension polymerization, and electrohydrodynamic atomization, allow precise control over microsponge properties, optimizing drug loading and release kinetics. In arthritis, microsponges extend anti-inflammatory activity; in IBD, they enable colon-specific delivery; and in psoriasis, they enhance drug penetration through keratinized plaques. These systems improve patient compliance by reducing dosing frequency and minimizing adverse effects. Despite their promise, further research is needed to optimize formulations, evaluate long-term safety, and fully explore their potential in managing chronic inflammatory diseases. Microsponge technology offers a transformative platform for improving therapeutic outcomes, paving the way for innovative treatments in pharmaceutical and clinical applications.

The global increase in allergic diseases, such as atopic dermatitis, allergic rhinitis, asthma, and food allergies, has become a major public health issue. These diseases typically involve immune dysregulation, including a Th1/Th2 imbalance, increased IgE levels, regulatory T cell (Treg) dysfunction, and epithelial barrier dysfunction. New research has recognised an important role for the gut and mucosal microbiome in regulating immune responses and has prompted interest in the therapeutic utility of probiotics. Probiotics are live microbes that, when given in adequate amounts, confer health benefits, generally such as immunomodulation or restoration of gut barrier function. Traditional probiotics (i.e., Lactobacillus and Bifidobacterium species) reduce allergic inflammation through promotion of Treg differentiation, increases in antiinflammatory cytokines (e.g., IL-10), suppression of Th2 cytokines (e.g., IL-4), and modification of IFNγ. Traditional probiotics also support mucosal barrier function and restore microbial composition by producing short-chain fatty acids (SCFAs), like butyrate, which act directly on Gprotein- coupled receptors and histone deacetylases to suppress inflammation. Next-generation probiotics (NGPs), such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides fragilis, and some clusters of Clostridia, can provide more targeted effects. These NGPs can secrete anti-inflammatory metabolite compounds, such as polysaccharide A (PSA), which modulate dendritic cells and increase Treg activity, and can promote mucin production to improve gut barrier function. Overall, there are key issues with strain specificity, dose, safety in immunocompromised individuals, and possible regulatory classification issues. Future opportunities may include precision microbiome profiling, synthetic biology, and artificial intelligence-driven strain discovery to develop personalised approaches to allergy immunotherapy.

Introduction: The present study focused on the formulation of a Sertaconazole Nitrate (SN) organogel with neem seed oil through microwave irradiation, optimizing the formulation by Box-Behnken Design (BBD) and Response Surface Methodology (RSM). The research explored the effect of Neem Seed Oil (NSO), Carbopol-934 (CP), and Polyethylene glycol-400 (PEG) on viscosity (VS), spreadability (SP), and drug content (DC).

Methods: A 15-run BBD was utilized to investigate the impact of the independent variables. The organogels obtained were analyzed for viscosity, spreadability, and drug content. The optimized formulation was also characterized for homogeneity, pH, swelling index, extrudability, drugexcipient compatibility, moisture content, and gel-sol transition temperature (GSTT). In-vitro and ex vivo release studies and antifungal activity against Candida albicans and Trichophyton rubrum were also carried out.

Results: The measured viscosity (0.40±11 Pa.s), spreadability (14.98 ± 74 gm.cm/sec), and drug content (97.11 ± 27 %) of the optimized formulation were very close to the calculated values. The optimized organogel had a skin-compatible pH (6-7), high in-vitro (98.55±0.32%) and exvivo (88.95 ± 1.55 %) drug release, and a wider zone of inhibition (22 mm) against Candida albicans and Trichophyton rubrum than a commercial product.

Discussion: The microwave-irradiation-synthesized BBD-optimized SN organogel with neem oil showed excellent drug release (>98%), skin-friendly pH, and improved antifungal activity (22 mm inhibition) compared to commercial preparations in line with green pharmaceutical trends. The scalability of microwave procedures, stability over extended periods, and sparse excipient screening require investigation to extend laboratory success to clinical application.

Conclusion: The research was able to successfully develop and optimize a Sertaconazole Nitrate organogel through a microwave-assisted process with a natural oil. The optimized formulation was found to have good physicochemical parameters, drug release behavior, skin compatibility, and improved antifungal activity, which implies its suitability for effective topical drug delivery.

Diabetes mellitus, a complex metabolic disorder, proves to be a challenge for the population around the world, as it includes chronic inflammation, oxidative stress, and glucose dysregulation. Resveratrol is a naturally occurring compound that acts as a diabetes complication- mitigating agent through complex cellular maneuvers and acts specifically to remedy diabetes complications. This review focuses on the action of resveratrol, underlining its vital impact in the alteration of significant pathophysiological pathways in diabetes. Besides, the activation of the AMPK and SIRT1 pathways also greatly improved cellular stress responses as well as insulin sensitivity. Numerous clinical studies have validated that the implementation of natural polyphenols' supplementation enhances glucose control, diabetes, inflammation, and insulin sensitivity, which supports these study findings. Its clear safety profile and flexible bioavailability also enhance its position as an adjunct diabetes therapy. As promising as that is, some issues still need to be addressed, including tackling standardized challenges like dosage issues and bioavailability.

Introduction: Cichorium intybus, a biennial plant belonging to the Asteraceae family, has been widely utilized in traditional Indian medicine for its tonic, anti-acne, anti-inflammatory, antioxidant, and hepatoprotective properties. Despite its known medicinal benefits, the bioactive compounds responsible for these activities require further exploration to validate their therapeutic potential. Our aim is to investigate the molecular docking interactions and antioxidant potential of an isolated bioactive compound from Cichorium intybus seeds, with a focus on its role in mitigating oxidative stress and inflammation in the liver.

Methods: The compound was isolated using ethanol extraction, followed by phytochemical screening, TLC, column chromatography, and identification through FTIR, NMR, and mass spectroscopy. Molecular docking studies were conducted using Schrödinger Suite to analyze interactions with PPARα. Antioxidant activity was evaluated using DPPH and ABTS radical scavenging assays, with results compared through Trolox Equivalent Antioxidant Capacity (TEAC) values.

Results: Esculetin, the isolated compound, exhibited strong binding affinity with PPARα (XP GScore: -7.0 kcal/mol). Antioxidant assays showed moderate activity, with DPPH radical scavenging activity (RSA) of 10.37% and ABTS RSA of 7.445%. The TEAC values were 13.23 μmol/mg and 21.930 μmol/mg, respectively, indicating its potential antioxidant efficacy.

Discussion: Esculetin from Cichorium intybus showed moderate antioxidant activity and strong PPARα binding, indicating its potential as a therapeutic agent. These findings align with existing research but require validation through in vivo studies to confirm efficacy and elucidate biological mechanisms.

Conclusion: Esculetin demonstrates significant potential as a bioactive antioxidant and antiinflammatory agent, supporting its relevance for further pharmacological and therapeutic investigations.

Introduction: Trans-resveratrol is a bioactive polyphenol that has been widely studied for its antioxidant, anti-inflammatory, and chemoprotective properties. It holds promise in pharmaceutical and nutraceutical formulations but is limited by poor bioavailability and stability.

Methods: This review synthesizes validated analytical methods for quantifying trans-resveratrol across various matrices. A comprehensive literature search (2000-2024) was conducted using PubMed, Scopus, and Google Scholar, focusing on RP-HPLC, HPTLC, GC, and UV spectroscopy. Method validation follows ICH guidelines.

Results: Thirty-seven validated analytical methods were reviewed. RP-HPLC using C18 columns with acetonitrile-water mobile phases dominated the literature. The most sensitive technique identified was LC-MS/MS (LOD = 0.001 μg/mL), particularly effective in biological samples. Matrix types included wine, serum, and nanoparticle formulations.

Discussion: RP-HPLC and LC-MS/MS have emerged as robust techniques for resveratrol quantification due to their sensitivity and specificity. Emerging tools like biosensors and UPLC offer rapid analysis with lower solvent consumption. Challenges such as isomerization, photodegradation, and matrix interferences necessitate stringent sample-handling protocols.

Conclusion: Advanced chromatographic methods, especially RP-HPLC and LC-MS/MS, are essential for the reliable quantification of trans-resveratrol. Future research should focus on analytical standardization and the development of novel delivery systems to enhance resveratrol's pharmacokinetic profile.