Abstract: Marine triterpenoid saponins are structurally diverse metabolites with high pharmacological and nutraceutical potential, yet their characterization remains challenging due to extensive isomerism, aggregation phenomena, and the frequent co-extraction of lipids and other matrix components. In this work, we combine ATR–FTIR and high-resolution LC–MS to investigate the spectral and chromatographic behaviour of Cucumaria frondosa extracts and butanol-enriched fractions. FTIR spectra reveal a strong aliphatic signature, N–H-related features, and ester carbonyl bands consistent with the presence of co-extracted lipids and nitrogen-containing species such as ceramides or sphingolipids. LC–MS analysis of preparative fractions shows recurrent saponin-like ions— most prominently a feature at m/z≈1347—reappearing across chromatographically distinct fractions, often accompanied by lipid-like ions in the 600–900 m/z range. These observations indicate that closely associated lipidic species can modulate the apparent chromatographic behaviour of saponin-containing fractions.

Abstract: Osteoarthritis (OA) is a prevalent chronic pain syndrome and a leading cause of disability worldwide, characterized by progressive deterioration of articular cartilage. This degradation leads to pain, swelling, inflammation, and eventual stiffness as the cartilage wears down, causing bone-on-bone friction. Current medical treatments primarily aim at pain relief; however, many interventions, especially invasive or surgical ones, carry risks of adverse outcomes. Consequently, intra-articular (IA) therapy, particularly hyaluronic acid (HA) injections, is widely adopted as a conservative treatment option. HA plays a crucial role in maintaining joint homeostasis by supporting proteoglycan synthesis and scaffolding, restoring optimal HA concentrations in synovial fluid, and providing chondroprotective and anti-inflammatory effects. In recent years, hydrogels composed of natural and synthetic materials have emerged as promising candidates for OA treatment. Our research focuses on the biosynthesis and characterization of novel hydrogel composites combining short peptide hydrogelators with aminated graphene oxide (a-GO) nanosheets functionalized with HA (a-GO-HA@Hgel). These a-GO-HA@Hgel nanocomposites are designed to facilitate the controlled release of HA into the extracellular matrix, aiming to promote cartilage regeneration and mitigate inflammation. The strategy is to exploit the oxygen-containing functional groups of GO nanosheets to enable covalent coupling or physical adsorption of HA molecules through various chemical approaches. The resulting a-GO-HA are incorporated within hydrogel matrices to achieve sustained and controlled HA release. We study the influence of a-GO-HA on the native hydrogel structure and its viscoelastic properties, which are critical for mimicking the mechanical environment of native cartilage tissue. Through this multidisciplinary approach combining advanced materials science and cellular biology, this work aims to develop innovative nanocomposite hydrogels capable of delivering HA in a controlled manner, enhancing cartilage repair and providing a potential therapeutic strategy for OA management.

Abstract: We herein demonstrate that the thiosemicarbazone (TSC) ligand N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) can coordinate with Ga3+ to give the cationic complex of [Ga(L)2]NO3 featuring an the octahedral Ga(III) center. [Ga(L)2]NO3 may undergo metathesis with both Fe2+ and Fe3+ and result in the formation of respective Fe2+- and Fe3+ complex. Meanwhile, [Ga(L)2]NO3 is also susceptible to anion exchange with solidum hyaluronate (NaA) to produce the nanoformulation of [Ga(L)2]A with boosted aqueous solubility and cell targetability. [Ga(L)2]A demonstrated remarkable in vitro cytotoxicity against NCI-H82 and A549 (lung cancer), as well as KYSE-510 and Te-1 (esophageal cancer) cell lines, featuring half maximal inhibitory concentration (IC50) values in the range of 0.102 − 2.616 μmol L−1. This work highlights the potential of using non-toxic and biocompatible Ga3+ as the central ion to prepare TSC-based nanomedicines for combating cancer.

Abstract: Expanding the chemical diversity of DNA-encoded libraries (DELs) is crucial for identifying binders to emerging drug targets using DEL technology. In the present study, as part of our ongoing efforts to develop on-DNA diazide platforms (D-DAPs)—platform molecules possessing both aromatic and aliphatic azide groups on a single core reactive scaffold—we have designed and synthesized a new compact diazide platform, designated as a compact D-DAP (C-D-DAP). This molecule is based on a low-molecular-weight reactive scaffold, 3-azido-5-(azidomethyl)benzoic acid, to facilitate small-molecule drug discovery targeting enzymes and G protein-coupled receptors (GPCRs). Furthermore, we established two distinct stepwise warhead construction strategies that exploit the chemoselective transformations of the azide groups in the C-D-DAP, which exhibit different reactivities. In addition, four virtual DELs were generated based on stepwise warhead elaboration from the C-D-DAP scaffold. Comparative chemical diversity analysis against bioactive compounds from ChEMBL revealed that these virtual libraries populate structural regions that are sparsely represented among known molecules. Each virtual library also occupies a distinct region of structural space relative to the others and displays intermediate quantitative estimate of drug-likeness (QED) values.

Abstract: Hypertension is a leading global health burden, with dihydropyridine calcium channel blockers (DHP CCBs) serving as a primary therapeutic class. However, the molecular and pharmacokinetic determinants underlying their variable clinical efficacy remain incom-pletely understood. This in silico study investigated the structural and ADME basis for the differential activity of five DHP drugs (amlodipine, nifedipine, isradipine, nicardipine, nisoldipine) targeting the L-type calcium channel CaV1.2. Molecular docking (Glide-XP), MM-GBSA binding free energy calculations using the human CaV1.2 structure (PDB: 8WE8), and ADME predictions (QikProp, CYP3A4 site of metabolism) were integrated. Results identified a conserved hydrogen bond with residue SER1132 (bond length range: 1.931–2.094 Å) as a key binding anchor. The Coulombic interaction energy (range: -74174.2 to -74202.3 kcal/mol) showed a strong inverse correlation with experimental IC₅₀ (0.013–0.194 µM), establishing it as a primary affinity determinant. Pharmacokinetically, predicted human serum albumin binding (QPlogKhsa: 0.237–0.770) directly correlated with IC₅₀, and metabolic vulnerability to CYP3A4 varied notably among the drugs. These findings demonstrate that the differential potency of DHP CCBs arises from a combination of target engagement strength, governed by electrostatic interactions and a conserved SER1132 anchor, and key ADME properties, providing a computational framework for ra-tional antihypertensive drug design.

Abstract: The development of Multi-Target-Directed Ligands (MTDLs) offers a compelling therapeutic strategy for multifactorial diseases like cancer and Alzheimer's disease (AD), which share pathological pathways, notably microtubule abnormalities. This study introduces and validates a state-of-the-art computational pipeline, the QSAR-MD-DCCM workflow, designed to accelerate the discovery of dual-acting agents targeting tubulin polymerization and acetylcholinesterase (AChE). Two highly predictive QSAR models (R2 > 0.83), built upon the trimethoxyphenyl scaffold, guided the rational design of 16 novel compounds. Subsequent ADMET screening identified compounds 15 and 16 as optimal leads, demonstrating excellent physicochemical properties and CNS penetrability. Molecular docking and rigorous 100 ns Molecular Dynamics (MD) simulations confirmed strong, persistent binding to both targets (PDB ID: 4O2B for tubulin; 1EVE for AChE), with the compounds showing complementary, target-differentiated potency. Subsequent MM-GBSA/MM-PBSA binding free energy calculations provided the essential energetic validation, confirming highly favorable binding for both leads. Crucially, Dynamic Cross-Correlation Map (DCCM) analysis provided novel mechanistic insights into the functional allosteric coupling of residues upon ligand binding, reinforcing the stability and distinct dynamic modes of action for both compounds. This integrated methodological approach successfully delivered two highly validated virtual MTDL candidates, establishing a robust and predictive platform for accelerating dual-target drug discovery.

Abstract:

Equinin B (GQCQRKCLGHCSKKCPKHPQCRKRCIRRCFGYCL), a marine peptide from Actinia equina exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria. To identify a smaller active region, the peptide was cleaved into three fragments: GQCQRKCLGHCS (EB-1), KKCPKHPQCRK (EB-2) and RCIRRCFGYCL (EB-3). Only the 11-residue C-terminal fragment showed selective activity against Gram-positive bacteria, including Staphylococcus epidermidis, Bacillus subtilis, and Enterococcus hirae, while remaining inactive against Escherichia coli. Peptide modifications, achieved by replacing cysteine residues with arginine, generally did not enhance activity, but in the C-terminal fragment they reduced hemolytic activity and increased bacterial specificity. Membrane depolarization assays confirmed that the unmodified fragment strongly disrupts bacterial membranes, whereas the modified variant showed minimal depolarization, highlighting its markedly reduced membrane-disruptive potential. In silico modelling revealed that the unmodified fragment (EB-3) can adopt multiple membrane-disruption modes, from transient shallow pores to carpet-like mechanisms, while the cysteine-to-arginine variant interacts mainly via partial insertion anchored by arginine residues. Phenylalanine appears to interact with the membrane, and reducing hydrophobicity by its removal abolished antibacterial activity. These findings highlight the 11-residue C-terminal fragment as a tunable, membrane-targeting motif with mechanistic novelty, offering a blueprint for developing safer, selective antimicrobial peptides with reduced cytotoxicity.

Abstract: Background/Objectives: Escalating resistance to existing antifungal compounds necessitates development of novel bioactive molecules with innovative mechanisms. Paclobutrazol, a triazole-containing plant growth regulator with modest antifungal activity, presents a structurally versatile scaffold amenable to derivatization. This study investigated whether strategic structural modifications could enhance antifungal potency and reveal broader therapeutic applications through integrated computational approaches. Methods: Twenty-six novel paclobutrazol derivatives were synthesized via etherification or esterification and characterized through NMR spectroscopy (¹H, ¹³C, ¹⁹F), IR spectroscopy, and mass spectrometry. Computational assessment employed CropCSM for toxicity prediction, pdCSM-GPCR for G protein-coupled receptor affinity estimation, MolPredictX for pathogenic target activity probability, CB-Dock2 for molecular docking, and pkCSM for ADME properties and drug-likeness evaluation. Results: Compound 26, featuring naphthyl substitution, demonstrated strong binding to sterol 14-alpha demethylase (-10.8 kcal/mol), calcitonin gene-related peptide type 1 receptor (-11.1 kcal/mol), extracellular calcium-sensing receptor (-10.9 kcal/mol), and metabotropic glutamate receptor 4 (-10.4 kcal/mol), with CGRP1R affinity comparable to approved antagonist rimegepant (-11.3 kcal/mol). Compounds 18 and 19, containing nitro groups, were the only substances predicted to exhibit AMES toxicity. Multiple derivatives showed activity against fungal, bacterial, parasitic, and viral targets. Compounds 20-22 displayed favorable drug-like properties with balanced physicochemical parameters. Conclusions: This work establishes paclobutrazol as a viable scaffold for therapeutic development beyond traditional antifungal applications. The analysis suggests potential utility in migraine and pain management through CGRP receptor modulation, calcium homeostasis disorders via calcium-sensing receptor targeting, neuroendocrine conditions through somatostatin receptor type 5, and inflammatory diseases via prostaglandin D2 receptor 2. These findings provide a framework for repurposing agricultural compounds in drug discovery, though further experimental validation is required.

Abstract: Boron-dipyrromethene (BODIPY) dyes belong to a class of organoboron compounds that have become ubiquitous for researchers in areas of fluorescence imaging, photodynamic therapy, and optoelectronics. The intrinsic qualities of BODIPY dyes and their me-so-modified structural analogs, Aza-BODIPY dyes, have propelled their recent increase in use in biomedical applications. The two scaffolds have high quantum yields, narrow absorption and emission bandwidths with large Stokes’ shifts, and high photo- and thermal stability. Because their properties are independent of solvent polarity and dye functionality, they can be tuned to promote novel analytical methods, resulting in the adaptation of the physicochemical and spectral properties of the dyes. In this review of BODIPY and Aza-BODIPY scaffolds, we will summarize their spectral properties, synthetic methods of preparation, and applications reported between 2014 and 2025. This review aims to summarize the advances in chemosensing, especially pH sensor development, and the advances in NIR-II window bioimaging probes. We hope that this succinct overview of Aza-BODIPY scaffolds will highlight their untapped potential, elucidating insights that may catalyze novel ideas in the physical organic realm of BODIPY.

Abstract:

Functionalized mesoporous silica particles were synthesized via a simplified sol–gel co-condensation method using mixed silica precursors—tetraethoxysilane (TEOS) and (3-mercaptopropyl) triethoxysilane (MPTES)—in two different molar ratios, alongside a reference non-functionalized MCM-41 sample. The obtained materials were characterized by nitrogen adsorption–desorption (BET–BJH–DFT) to assess their textural properties. The results confirmed a significant decrease in surface area and pore volume upon functionalization (from 1213 to 72.35 and 16.06 m² g⁻¹), accompanied by narrower pore diameters (2.4–3.5 nm), indicating partial pore blocking and increased surface tortuosity in the M1 and M2 samples. All materials demonstrated excellent carrier capacity for the hydrophobic antifungal drug clotrimazole (CLZ), achieving loading efficiencies close to 99% in all tested solvent media. The release behaviour was evaluated in acidic and mildly acidic environments (0.1 N HCl, KCl–HCl buffer pH 2, and acetate buffer pH 4.5). The best performance was observed when the same buffer was used for both drug loading and release, with cumulative release values between 51–91% at pH 2, while release remained in the 11–20% range at pH 4.5 and around 45% in 0.1 N HCl after 6 h. These findings highlight the influence of surface chemistry and pore architecture on drug–matrix interactions, confirming the potential of thiol-functionalized silica carriers for controlled delivery of hydrophobic drugs under pH-relevant conditions. The measured release time was evaluated for 24 hours via classical evaluation and for 3 hours and 20 minutes for the experiments performed with the dissolution instrument. The water: propan diol mixture solution has been chosen in order to mimic the pH of the skin level conditions. The different acidic solution has been chosen in order to mimic the acidic pH around a cancercell or around an inflammation. The extreme pH conditions (1 or 2) were chosen in order to model the dissolution of a drug with very low water solubility in an acidic environment. Moreover, these systems are very rarely studied in the literature.

Abstract:

Oxytocin (OXT) has demonstrated potential therapeutic effects in Alzheimer’s disease (AD) through mechanisms such as reducing amyloid-β (Aβ) accumulation and tau deposition, as well as exerting antioxidant and anti-inflammatory properties. A recent study further revealed that OXT can decrease acetylcholinesterase (AChE) activity in liver and kidney tissues, suggesting that its effects on Aβ and tau pathology may be mediated, at least in part, through AChE inhibition. Based on this rationale, a series of OXT derivatives were designed, synthesized, and evaluated using protein-protein interaction analysis, molecular docking, in vitro AChE inhibition assays, enzyme kinetics, and antioxidant assays. Docking and protein-protein interaction studies showed that OXT and its analogues fit well within the 20 Å gorge of the AChE active site, engaging both the catalytic active site (CAS) and the peripheral anionic site (PAS). In vitro AChE inhibition assays revealed promising activity, with OXT (Cmpd.16) and analogue 7 (Cmpd.7) exhibiting IC₅₀ values of 8.5 µM and 3.6 µM, respectively. Kinetic analysis determined inhibition constants (Kᵢ) of 45 µM for Cmpd.16 and 6 µM for Cmpd.7, with both compounds following a mixed-type inhibition mechanism. Furthermore, antioxidant evaluations indicated potential neuroprotective properties. In conclusion, OXT analogues act as dual-binding site AChE inhibitors, as supported by docking, protein-protein interaction, and kinetic analyses, and display greater inhibitory activity than OXT itself. These findings suggest that OXT analogues represent promising candidates for further development as AChE inhibitors for AD therapy.

Abstract: Natural products are sources of secondary metabolites with various biological activities. This review highlights the promising potential of the Annonaceae family, a large clade of flowering plants with 107 genera and over 2300 species. Known for their vast pharmacological activities, several genera and species within this family are considered excellent sources of bioactive molecules due to the diversity of their secondary metabolites. Chemical investigations have revealed the presence of alkaloids, mainly isoquinolinic alkaloids, phenolic compounds, terpenoids, lactones, and acetogenins. The Annonaceae family exhibits anti-inflammatory, insecticidal, antimicrobial, leishmanicidal, cytotoxic, antitumor, trypanocidal, antioxidant, gastroprotective, and antimalarial activities. However, most studies focus on plant extracts and essential oils, with few isolated molecules and mechanisms of action identified. Investigating the biological activity of isolated compounds is crucial for new drug discovery. This review also compiles important information for the pharmaceutical and agricultural industries.

Abstract: Neglected tropical diseases (NTDs) remain a significant global health burden, exacerbated by the ongoing climate emergency, which alters disease distribution and increases vulnerability in affected populations. The urgent need for novel therapeutics demands innovative approaches in drug discovery, with heterocyclic compounds serving as versatile scaffolds due to their diverse electronic and structural properties that enable potent biological activity. This review highlights the integration of green chemistry principles in the synthesis of bioactive heterocyclic scaffolds for NTD drug development. Key sustainable methodologies are discussed, including microwave-assisted solvent-free and green-solvent reactions, ultrasound-assisted synthesis, mechanochemical one-pot multistep strategies, and the use of ionic liquids and deep eutectic solvents as environmentally benign catalysts and reaction media. By focusing on these approaches, the review emphasizes how green synthetic strategies can accelerate the development of pharmacologically relevant heterocycles while minimizing environmental impact, resource consumption, and hazardous waste generation.

Abstract: Arzanol, a prenylated phloroglucinol–α-pyrone heterodimer, displays a broad range of pharmacological properties. This review compiles findings from 2007–2025 on its chemistry, conformational behavior, bioactivities, molecular targets, and pharmaco-kinetics. Conformational flexibility, driven by intramolecular hydrogen bonding, ena-bles multitarget interactions. Arzanol shows potent anti-inflammatory activity through NF-κB inhibition and dual suppression of mPGES-1 and 5-LOX, antioxidant and cytoprotective effects via radical scavenging and metal chelation, and selective antibacterial activity. Arzanol also modulates autophagy, mitochondrial function, and metabolic pathways, with high-affinity binding to brain glycogen phosphorylase and SIRT1. Pharmacokinetic data indicate gastrointestinal stability, intestinal absorption, and limited blood–brain barrier penetration. In vivo, arzanol exhibits neuroprotective, neurobehavioral, and metabolic effects, while showing selective cytotoxicity toward cancer cells with minimal impact on normal cells. This review critically evaluates the diverse biological activities of arzanol, analyzing the relationship between its unique conformational flexibility and multitarget pharmacological effects.

Abstract: Benign prostatic hyperplasia (BPH) is a multifactorial disease associated with chronic inflammation, oxidative stress, and androgenic imbalance. Dysphania ambrosioides (L.) Mosyakin & Clemants contains flavonoids and phenolic acids with well-recognised antioxidant and anti-inflammatory properties; however, its potential activity against the molecular targets of BPH has not been systematically evaluated. A comparative quantitative analysis was performed using studies published between 2005 and 2025 that reported antioxidant activity (DPPH assay, IC₅₀ in µg/mL) of D. ambrosioides extracts. Metabolites from extracts with IC₅₀ values below the global mean (398.410 ± 81.810 µg/mL; n = 35) were selected for in silico prioritisation using OSIRIS, PASS, and ProTox 3.0, followed by molecular docking (CB-Dock2) against AR, 5AR2, COX-2, NLRP3, and α1A receptors. Luteolin and rosmarinic acid exhibited favourable binding affinities (-9.5 to -7.7 kcal/mol) comparable in magnitude to pharmacological controls (finasteride -13.4, celecoxib -11.4, tamsulosin -7.3 kcal/mol). Rosmarinic acid was particularly effective on androgenic targets, whereas luteolin showed higher affinity for inflammatory and adrenergic targets. This study integrates, for the first time, a quantitative assessment of antioxidant activity with a multitarget in silico evaluation of D. ambrosioides, prioritising luteolin and rosmarinic acid as natural candidates with potential antioxidant, anti-inflammatory, and antiandrogenic properties relevant to BPH and prostatitis.

Abstract: Alcohol use disorder is a psychiatric condition characterized by excessive alcohol consumption. The drugs that are used to treat it often fail to prevent relapse. At the same time, psilocybin is increasingly being investigated for the treatment of various substance use disorder. This review aims to evaluate the results of the most recent clinical trials assessing psilocybin as a treatment for alcohol use disorder. According to these trials, psilocybin seems to reduce craving but its effect on overall alcohol consumption is less clear. There is no doubt that future trials would benefit from larger sample sizes and standardized tests.

Abstract: Herein, a co-adsorption modification based on ZIF-8 was introduced with the contribution of PEG package to enhance the antioxidant potency of the Hedysari Radix disperse particles. In the solution system containing 15% ethanol, the rough surface of the original Hedysari Radix disperse particles (HRE) was improved by the typical co-adsorption modification with ZIF-8 (HRE@ZIF-8 3) and further smoothed by the package of PEG (HRE@ZIF-8@PEG 3). The co-adsorption modifications including ZIF-8 only, PEG only, and ZIF-8 with PEG were all studied in the solution system. In particular, the modification combined both the PEG package and suitable amount of ZIF-8 achieved the most significant enhancement of the CAT activity as well as the T-AOC value. HRE@ZIF-8@PEG 3 alleviated the oxidative stress upon C. elegans and extended the survival time. This work suggested meaningful co-adsorption modification for improving the potency of the medicinal plant resources.

Abstract:

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by intracellular enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent this limitation, several prodrug approaches have been proposed and developed. Herein, we hypothesized that the conjugation of anti-HIV fatty acids with the nucleotide tenofovir alafenamide (TAF) (1) could improve the anti-HIV activity of the nucleotide. Several fatty acyl amide conjugates of TAF were synthesized and evaluated in comparative studies with TAF. The synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single-round HIV-1 infection assay using TZM-bl cells at concentrations ranging from 0.01 to 100 ng/mL. Tetradecanoyl TAF conjugate 10 and palmitoyl TAF conjugate 17 had higher CLogP and displayed comparable activity to TAF (96-99% inhibition at 10–100 ng/mL) but at lower molar concentrations. The IC50 of conjugate 17 (0.65 nM) was lower than that of TAF (1.06 nM); however, this difference was not statistically significant.

Abstract: Metal complexes have been utilized in medicine for thousands of years in a variety of ways, with positive benefits and well recognized as anti-infective, anti-inflammatory, antimicrobial, antidiabetic, neurological agents, delivery prob and diagnostic agents. Based on that Co, Zn, Cu complexes were synthesized and fully characterized. The complexes were then assessed with MDA-MB-453, human breast cancer cell line and the data showed that Cu- ligand complex was the most potent anticancer agent followed by Zn then Co complex. The DFT theoretical calculations were parallel with the biological assessment and support it. In addition, the complexes were tested for their biological activities in both gram positive and negative bacteria and the data revealed that Cu>Zn>Co with strong inhibitory effect on both bacterial growths. In sum, copper complex proved to be potent anticancer and antibacterial agent and can be used for future therapies.

Abstract: Alzheimer's disease involves oxidative stress in brain tissue, creating a need for stable neuroprotective agents. Anthocyanins are potent antioxidants, but they are highly susceptible to degradation. This study evaluated anthocyanins from purple corn (PCA) and camu-camu (CCA) and the copigmentation effects of the phenolic acids cinnamic (C), ferulic acid (F), resveratrol (R) and polyaspartic acid (P) on the stability and neuroprotective capacity of these anthocyanins. HPLC-MS analysis identified twelve anthocyanins in PCA, including two novel compounds. Copigmentation was assessed via UV-Vis spectroscopy, FTIR, TG, and stability tests at pH 7.4. The TBARS assay evaluated protection against oxidative stress in brain tissue. Copigment R provided the strongest hyperchromic effect for PCA, while P was most effective for CCA. TG analysis showed that copigmentation with R significantly improved the thermal and pH stability of both anthocyanin sources. All single copigmented systems showed improved stability of anthocyanins in physiological conditions. Furthermore, R-copigmented anthocyanins exhibited the most potent neuroprotective effects, significantly inhibiting lipid peroxidation. Thus, copigmentation, particularly with R, is a highly effective strategy for stabilizing anthocyanins and enhancing their potential as neuroprotective agents against oxidative stress.