A novel series of triazole-linked monoterpenoid-lignan based molecules was designed by employing a molecular hybridization strategy inspired by the pharmacophoric properties of eugenol (monoterpenoid) and its derivatives, and sesamol (lignan). Designed molecules were synthesised and evaluated for their xanthine oxidase inhibitory potential. Among the series of hybrid molecules, MT7 (isoeugenol-sesamol hybrid) showed the most potent xanthine oxidase inhibition (IC₅₀ = 0.263 µM) with a mixed-type of inhibitory pattern and scavenging reactive oxygen species in RAW 264.7 macrophage cells. Furthermore, higher cytotoxic potential of MT7 against xanthine oxidase harbouring cancer cells over non-harbouring cells (A547 skin cancer cells) and reduction in antioxidant enzymes confirms the binding pattern of MT-7 in Mo-cofactor (molybdenum cofactor) binding site. Molecular docking and simulations studies confirmed the stability and favourable interactions of MT7 with the febuxostat binding site of xanthine oxidase. MT7 was non-toxic to mouse fibroblast cells (L929) and showed stability with plasma and liver microsomes. MT7 further emerged as safer for in vivo preclinical investigations in rodent models with an LD₅₀ value of 300 mg/kg and showed dose dose-dependent reduction in serum uric acid in potassium oxonate oxonate-induced hyperuricaemia rat model. Overall, studies representing MT7 as high a highly efficaciousefficacy lead for further xanthine oxidase drug development initiatives, and a preclinical candidate with tolerable safety profiles for management of hyperuricemia via xanthine oxidase inhibition.

MRSA skin infection remains a serious health concern. Clindamycin, an FDA-approved lincosamide antibiotic, treats MRSA but is limited topically by the stratum corneum (SC) as a skin barrier. This study developed nanostructured lipid carrier (NLC) to improve clindamycin’s efficacy against MRSA wound infections. NLC was prepared using a cold microemulsion technique, optimized, and characterized for its physicochemical properties, with safety confirmed by an MTT assay in HaCat cells. Cinnamaldehyde was selected as the NLC’s oily phase due to its antibacterial properties, providing synergistic effects. The clindamycin-loaded cinnamaldehyde-based NLC exhibited a nanometric size of 100.3 ± 3.8 nm, a narrow size distribution (PDI 0.19 ± 0.0002), and a spherical morphology. In vitro antimicrobial activity was assessed on MRSA strains using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), biofilm inhibition, and regrowth bioassays. The loaded NLC enhanced antimicrobial activity against MRSA, showing 2- to 8-fold improvement over free clindamycin and unloaded blank NLC. MIC/MBC values were 1/4 μg/mL for the loaded NLC, 2/8 μg/mL for free clindamycin, and 8/64 μg/mL for blank NLC. At half the MIC concentration, the NLC inhibited MRSA biofilm formation by 67.58%, compared to 48.47% for free clindamycin. Skin permeation through SC was evaluated using Franz cells and showed improved drug permeation of the NLC formulation compared to the free drug. In vivo studies used Albino Wistar rats divided into five groups: uninfected, infected, untreated, infected treated with a marketed drug, infected treated with an unloaded formulation, and infected treated with a loaded NLC. After 7 days, agar cultures showed extensive bacterial growth in untreated rats, minimal growth in rats treated with unloaded formulation, and no growth in the loaded NLC group. Wound diameter measurements confirmed improved healing with the NLC, as analyzed using SPSS version 25. This formulation is a promising antibacterial vehicle against MRSA infections.

Introduction: Migraine is a highly prevalent and disabling neurological disorder commonly managed through monotherapy, which often provides insufficient symptom relief due to its multifactorial pathophysiology. Combination therapy emerges as a promising alternative by targeting multiple mechanisms simultaneously. Nanostructured lipid carriers (NLC) offer additional advantages, namely improved drug stability and enhanced bioavailability. In this work, two NLC formulations were developed, encapsulating zolmitriptan and ibuprofen, respectively, with the aim of combining them for intranasal administration, enabling direct nose-to-brain delivery. This strategy is expected to enhance therapeutic efficacy while offering a non-invasive and patient-friendly approach for the management of acute migraine.

Methods: The Quality by Design (QbD) approach was applied to optimize the NLC formulations with respect to the Critical Quality Attributes (CQAs) of particle size (Z-Ave), polydispersity index (PDI), zeta potential (ZP) and encapsulation efficiency (EE).

Results: The optimized zolmitriptan- and ibuprofen-loaded NLC exhibited Z-Ave, PDI, ZP, and EE values of 62.373 ± 0.567 nm and 141.333 ± 2.301 nm; 0.209 ± 0.008 and 0.205 ± 0.004; −52.463 ± 0.264 mV and −14.323 ± 0.652 mV; and 74.231 ± 0.646 % and 84.376 ± 1.594 %, respectively. Both were subsequently combined into a final formulation, which displayed suitable physicochemical properties for intranasal delivery: Z-Ave of 188.850 ± 2.333 nm, PDI of 0.233 ± 0.007, ZP of −16.297 ± 0.488 mV, osmolarity of 280 mOsm/kg, and pH of 6.06.

Conclusion: The QbD approach proved to be a valuable tool for optimizing both NLC formulations, resulting in suitable characteristics for nose-to-brain delivery. Future studies are needed to assess the cytotoxicity of the combined NLC formulation in nasal and neuronal cell lines, in order to evaluate its biocompatibility and safety for intranasal migraine therapy.

Introduction: Blood–brain barrier (BBB) penetration is a crucial factor to assess in central nervous (CNS) system drug development. This criterion is commonly expressed as the unbound brain-to-plasma ratio (K_p,uu,brain) determined through in vivo and in vitro methods (e.g., microdialysis, brain slices). Nevertheless, these experimental tests are costly and time-consuming, limiting their application in early drug discovery.

Methods: In this study, we present a novel hierarchical support vector regression (HSVR) model to predict log K_p,uu,brain values directly from molecular descriptors. A curated dataset with experimentally measured K_p,uu,brain values was utilized to develop and validate the in silico models.

Results: The HSVR ensemble model achieved high predictive performance with no signs of overfitting across training, test and outlier sets. In addition, it demonstrated robust performance in mock testing with independent datasets, confirming its broad applicability. Importantly, HSVR outperformed commonly used models such as the Brain Penetration Predictor and Brain Exposure Efficiency Score. Beyond quantitative prediction, HSVR also accurately classified BBB⁺ versus BBB⁻ compounds and achieved higher accuracy than SwissADME, lightBBB, and alvaRunner across multiple K_p,uu,brain cut-off thresholds.

Conclusions: Overall, HSVR provides a robust, interpretable, and cost-effective tool for predicting BBB penetration. It enables early decision-making, reduces reliance on animal testing, and accelerates the identification of CNS-targeted therapeutics.

The human ether-a-go-go-related gene (hERG) predominantly expresses in cardiac tissues causes long QT syndrome and blockade of this gene leads to cardiotoxicity. Medicinal chemists are working towards for discovering bioactive molecules without hERG blockage. Hence, many strategies have been implemented in last few decades including computational techniques for the design of novel molecules and the machine learning based classification analysis is predominantly used nowadays. In this investigation, 451 compounds with hERG blocking activity (experimental -LogIC₅₀), obtained from literature were considered in the study. For this analysis, the Decision Tree, Random Forest and Random Tree algorithms of WEKA software were applied. The results obtained from the analysis showed that the models developed with complete training set and validated by test set (30%) and 10-fold cross-validation methods provided significant statistical parameters. The contributed descriptors explained that the hERG blockers contain aromatic rings, such as phenyl (C₆H₅) or benzyl (C₆H₅CH₂) groups, which can participate in π-π interactions with aromatic residues in the channel. Basic nitrogen atoms, often found in primary (R-NH₂), secondary (R₂-NH), or tertiary (R₃-N) amines, are common in hERG blockers. Hydrophobic groups, such as alkyl chains (e.g., CH₃, C₂H₅) or cycloalkyl groups (e.g., cyclohexyl, C₆H₁₁), play a significant role by enhancing binding affinity to the hydrophobic pocket of the hERG channel. The presence of flexible linkers, such as ethylene (–CH₂–CH₂–) or propylene (–CH₂–CH₂–CH₂–) chains, between hydrophobic and hydrophilic parts of a molecule can facilitate optimal orientation within the binding site. Additionally, hydrogen bond donors (–OH, –NH₂) and acceptors (e.g., –CO, –CN) contribute to the binding affinity and specificity of a compound for the hERG channel, although they are less critical than hydrophobic and ionic interactions. This analysis provides information on the physicochemical properties required for the avoiding hERG blockade.

Abstract: The increasing problem of antimicrobial resistance (AMR) has made it more difficult to treat even common infections, especially Urinary Tract Infections (UTIs) and Bloodstream Infections (BSIs). These infections are often caused by bacteria resistant to multiple antibiotics, limiting treatment options. Among the most common pathogens responsible for these infections is Escherichia coli (E. coli), which has shown increasing resistance to several frontline antibiotics. In this study, multitargeted docking of the FDA-approved library from DrugBank was performed against crucial proteins from E. coli such as FimH (PDB ID: 1UWF), PNAG N-deacetylase (PDB ID: 4F9D), and Purine nucleoside phosphorylase (PDB ID: 4TS3) involved in UTIs, and BtuF (PDB ID: 1N4A), Uridine phosphorylase (PDB ID: 1RXC), and LpxH (PDB ID: 8QJZ) involved in BSIs. This study explored the potential of repurposing Dopexamine, a drug initially used to support heart function, as a possible solution to target key bacterial proteins involved in AMR. An in-silico approach was employed to investigate Dopexamine’s ability to inhibit mutated bacterial proteins associated with E. coli-mediated UTIs and BSIs. Comprehensive computational analyses were performed, including molecular docking to assess binding interactions, molecular dynamics (MD) simulations to evaluate complex stability, MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) calculations to evaluate binding free energies, Water Map analysis to understand hydration patterns, and Density Functional Theory (DFT) to investigate the electronic properties of Dopexamine. The results revealed favourable binding affinities, stable interactions, and promising physicochemical properties, indicating Dopexamine’s potential as a broad-spectrum inhibitor against AMR-related targets. These findings suggest Dopexamine as a valuable candidate for drug repurposing

Background: Cognitive impairment and dementia have become a global burden, distressing millions of elderlies, accounting for progressive loss of neurons in the brain affecting higher multiple cortical centers, and impacting social life. The renin-angiotensin system and its receptors, widely distributed within the brain, offer potential to treat dementia via diminishing oxidative stress, neuronal inflammation, and increasing blood-brain barrier (BBB) integrity. The present study delves into the formulation and optimization of thermoresponsive azilsartan medoxomil (AZL-M) loaded in situ nanoemulgel for targeted nose-to-brain delivery to the brain due to low BBB permeability and validated through in vivo models.

Methods: A Box-Behnken design was used to optimize formulation parameters such as droplet size, gelation temperature, and drug release. The optimized nanoemulgel was characterized for physicochemical properties and evaluated for ex-vivo nasal mucosal toxicity, in-vitro cytotoxicity, and ROS reduction. In-vivo efficacy of intranasal application of the optimized formulation was assessed in an AlCl₃-induced Alzheimer's model.

Results: Formulation-F20 showed optimal gelation at 33.4°C, pH-6.21, droplet size of 160nm, 60.4% drug release in 8h, high permeation, and flux, with confirmed safety and cell viability. TEER studies confirmed the integrity of RPMI-2650 monolayers, and while apparent permeability values of AZL-M solution and nanoemulgel were comparable, the nanoemulgel exhibited significantly higher cumulative permeation across the nasal epithelial barrier. In-vivo studies showed that nanoemulgel significantly improved cognitive performance and neuronal survival. At the molecular level, AZL-M treatment led to a marked reduction in brain inflammatory cytokines TNF-α and IL-1β, along with downregulation of Alzheimer’s-specific markers including phosphorylated tau, amyloid precursor protein, and NF-κB. Simultaneously, a significant upregulation of brain-derived neurotrophic factors indicated enhanced neurotrophic support and synaptic plasticity.

Conclusion: The intranasally delivered AZL-M-loaded nanoemulgel showed potential as a safe and effective therapy for Alzheimer’s dementia by attenuating neuroinflammation and Alzheimer’s pathology markers.

Background/Objectives: Sepsis remains a leading cause of global mortality despite advances in critical care, largely because treatment is initiated only after systemic inflammation and organ damage are already established. Emerging evidence highlights gut microbiota dysbiosis and intestinal barrier impairment as critical drivers of sepsis pathogenesis, particularly in immunocompromised patients. We propose that early modulation of the gut microbiome represents a viable prophylactic strategy against sepsis.

Methods: In this study, we designed and fabricated an advanced probiotic delivery platform based on ternary hydrogel microspheres, designated EcN+Muc@SHM. These microspheres were constructed by first encapsulating E. coli Nissle 1917 (EcN) and mucin within a methacrylated hyaluronic acid (HAMA) core via a photopolymerization-coupled emulsification method. Subsequently, a protective alginate shell was coated onto the surface through ion polymerization to enhance stability and targeted delivery.

Results: In vitro assessments demonstrated the potent bioactivity of the hydrogel components, wherein HAMA and mucin synergistically promoted intestinal cell proliferation, mitigated lipopolysaccharide (LPS)-induced mucus secretion injury in HT29-MTX cells, and alleviated inflammatory responses and oxidative stress in macrophages. Critically, the integrated EcN+Muc@SHM microsphere structure conferred robust protection to the probiotic EcN payload against the harsh gastric environment, as validated both in vitro and in vivo. In a clinically relevant cecal ligation and puncture (CLP) mouse model, this advanced probiotic platform exhibited remarkable prophylactic and therapeutic efficacy. Administration of the microspheres significantly reduced bacterial translocation, resolved local inflammation, and alleviated intestinal injury. Fecal microbiome sequencing further elucidated the underlying mechanism, revealing that the treatment effectively corrected post-CLP dysbiosis, thereby restoring microbial homeostasis and promoting the recovery of a healthy gut flora.

Conclusions: Our findings underscore the potential of proactive, microbiome-targeted strategies to disrupt the vicious cycle of dysbiosis and inflammation, offering a promising avenue for sepsis prevention in high-risk populations.

Background. By 2024, 14.1 million cases of dengue were reported around the world, folding the amount of 2023. Dengue is an orphan disease caused by the dengue virus (DENV), and it’s transmitted by mosquitoes such as Aedes aegypti, which has one of the highest reproductive rates and is more susceptible to the DENV-2 serotype. Scientific studies indicate that the envelope protein (EP) could be inhibited avoiding the viral fusion and interrupting the replication.

Method. EP was downloaded from PDB (1OKE code) and processed using PyMOL software. The scaffold was selected by searching for active chemical structures in ChEMBL from a study of 163 molecules. Molecular docking was performed using Autodock-Vina 1.1.2. The molecules with the highest activity were 36 and 136. In molecular dynamics the molecule 136 exhibited a better affinity, binding the amino acid THR48 of EP through the pharmacophore alpha-ethylidene thiohydantoin. One thousand one hundred thirty three bioisosteres were performed using alpha-ethylidene thiohydantoin scaffold with the Zinc 20 database. The bioisosteres were bring under molecular docking and four were selected.

Results. Molecules 1104, 1101, 1154, and 872 were found with better affinity than 136, they put through to molecular docking using Autodock Vina 1.1.2. SAR analysis of molecule 1104 show greater activity due to the ketone group, which influences the coplanarity of the heterocyclic cyclopentane, making better use of the pocket of the EP catalytic site and stabilizing by forming hydrogen bonds with AL50.

Conclusions. Four novel compounds of promising activity against envelope protein of dengue virus type 2 where found.

Introduction: Zein and fucoidan are biomaterials useful to obtain hybrid nanoparticles to be orally administered and employed for the treatment of inflammatory bowel disease (IBD). Zein is stable in gastrointestinal fluids while fucoidan confers mucoadhesion and intrinsic anti-inflammatory activity to the nanosystems.

Methods: Nanoparticles were obtained by nanoprecipitation using zein and fucoidan at various weight ratios and they were employed to entrap mesalazine (5-ASA). The physico-chemical properties, entrapment efficiency and release rate of the active compound in simulated gastrointestinal fluids were evaluated by dynamic light scattering, FT-IR and spectrophotometric analyses, respectively. The muco-adhesive interactions were assessed monitoring their mean diameter e and surface charge after incubation with porcine gastric mucin (0.1–0.5% w/v, 37 °C, up to 4 h). The antioxidant activity was investigated by the DPPH assay. Additional studies were performed in Caenorhabditis elegans in order to evaluate the in vivo fate of hybrid nanoparticles.

Results: Hybrid zein–fucoidan nanoparticles showed mean sizes of 100 nm, a narrow size distribution (PDI<0.2), a negative Zeta potential (ζ ≈ −55 mV) and an encapsulation efficiency of ~60% when 0.6 mg/mL of 5-ASA were used. They demonstrated to preserve the antioxidant activity of 5-ASA in simulated gastrointestinal fluid and the incubation with mucin confirmed the mucoadhesive properties of the nanosystems. In vivo studies in Caenorhabditis elegans showed a strong biocompatibility of the nanosystems, a useful intake and favorable effects on fat accumulation, oxidative stress and aging biomarkers.

Conclusions: Zein–fucoidan hybrid nanoparticles containing 5-ASA represent innovative nanomedicine to be employed for the treatment of IBD.