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.

Abstract: Medicinal plants serve as valuable reservoirs of bioactive compounds with therapeutic potential, offering alternatives in the fight against drug-resistant infections. Hyptis suaveolens (L.) Poit., though widely used in traditional medicine, remains underexplored despite reports of antimicrobial, anti-inflammatory, and other pharmacological activities. Given the global need for novel antimicrobials, this study investigated the volatile (essential oils) and non-volatile (methanolic) extracts of H. suaveolens leaves, aiming to assess their antimicrobial activity against selected bacterial and fungal pathogens. Fresh Hyptis suaveolens leaves were collected and authenticated at Adekunle Ajasin University, Nigeria. Essential oils were obtained via hydro-distillation, while methanolic extracts were prepared by maceration. Antimicrobial activity against clinical isolates (E. coli, P. aeruginosa, B. cereus, K. pneumoniae, and C. albicans) was assessed using agar well diffusion, with MIC and MBC determined through macro-broth dilution techniques. Hydro-distillation of fresh leaves yielded 2.7% essential oil, while methanol extraction of dried leaves produced 1.5% crude extract. Both extracts inhibited all six clinical isolates, with the methanolic extract showing greater efficacy. The highest inhibition zone was recorded against Candida albicans (32 mm), and the lowest against Staphylococcus aureus (27 mm). Minimum inhibitory concentration (MIC) testing revealed consistent activity of the methanolic extract across all concentrations, whereas the essential oil displayed variable inhibition. Minimum bactericidal concentration (MBC) assays confirmed bactericidal activity of both extracts, with E. coli and Pseudomonas aeruginosa eradicated at 25–50 mg/mL, while Klebsiella pneumoniae required the highest concentration (12.5 mg/mL). Hyptis suaveolens extracts exhibited broad-spectrum antimicrobial and bactericidal activity, with methanolic extract showing superior potency, highlighting its potential as a natural alternative antimicrobial source.

Abstract: Lapatinib is an approved therapy for HER2-positive breast cancer. It has a high affinity for the non-receptor cytoplasmic tyrosine kinases of the EGFR and HER2 receptors. It is a reversible type II inhibitor, with Kiapp values ​​of 3 nM and 13 nM, respectively. The dissociation rate of the lapatinib–receptor complex is notably slow compared with many other kinase inhibitors.. Although the literature contains numerous reports on radiolabelled ligands for HER-family receptors, studies on radiolabelled tyrosine kinase inhibitors are far fewer and only few focus specifically on radiolabelled lapatinib. The aim of this review is to compile and discuss the chemical and biological data on lapatinib-based radiopharmaceuticals with potential applications in the diagnosis and treatment of HER2-positive tumors.

Abstract: Tyrosinase is a key enzyme in melanogenesis, playing an important role in skin, hair, and eye pigmentation, as well as in the enzymatic browning of fruits and vegetables. Excessive tyrosinase activity leads to hyperpigmentation and other dermatological problems, and also causes losses in the food industry. For this reason, tyrosinase inhibitors have become the subject of intensive research in medicine, cosmetology, and food technology. Among the various inhibitors, compounds containing ketone and hydroxyl groups draw special attention, because they have the ability to chelate copper ions in the active center of enzyme or block an access to it.. This article discusses the possible mechanisms of action, based on molecular modeling of interaction of pdb database retrieved model of enzyme with known natural inhibitors – kojic acid and tropolone as well as newly synthesized and tested 6-hydroxyimino derivatives of imidazo[1,2-a]imidazole-5-ones. Results suggest that model of enzyme-ligand interaction can be useful in establishing affinity to tyrosinase of new natural and synthetic inhibitors. They can have broad applications in various fields, including melanoma therapy, and prospects for further development.

Abstract: Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce water solubility of the molecules, which is a disadvantage during application. To address this problem, azaborine rings may be substituted for conventional aromatic ring systems. These are obtained by replacing two adjacent carbon atoms with boron and nitrogen. Incorporating B–N analogues in place of aromatic rings not only enhances structural diversity but also provides a strategy to navigate around patent-protected scaffolds. We synthesized azaborines, which are isosteric to naphthalene and indole and utilized them as capping units for HDAC inhibitors. These molecules were attached to various aliphatic and aromatic linkers with different zinc-binding units, used in established active compounds. Nearly half of the 24 molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three com-pounds displaying IC₅₀ values in the nanomolar range. We have therefore demon-strated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop ac-tive substances containing azaborine rings against other targets.

Abstract:

Background/Objectives: Sulphonylureas (SUs) are a cost-effective first-line treatment for Type 2 Diabetes Mellitus (T2DM), yet the precise bioorganic mechanisms governing their activity and the variation in their hypoglycemic effects are not fully elucidated. This study aimed to computationally determine the structural basis for the activity of SUs on the sulphonylurea receptor 1 (SUR1) and to identify the factors responsible for their differing potencies and durations of action. Methods: A computational chemistry approach was employed to analyze first- and second-generation sulphonylureas. The methods included molecular docking to simulate drug-receptor binding, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations to estimate binding free energies, and the prediction of cytochrome P450 (CYP450) sites of metabolism to assess metabolic stability. Results: Molecular docking identified critical interactions between all SUs and the amino acid residues ARG 1300, ARG 1246, and ARG 4 on SUR1. The total hydrogen bond energy was found to be inversely proportional to the drugs’ potencies. Furthermore, the intrinsic reactivity of the predicted CYP450 metabolism sites was inversely proportional to the drugs’ observed half-lives. Conclusions: The activity of sulphonylureas on SUR1 is primarily driven by interactions with key arginine residues (ARG 1300, ARG 1246, and ARG 4). The variation in drug potency is explained by differences in total hydrogen bond energy, while the diversity in their hypoglycemic durations is attributed to their differing metabolic stability as determined by CYP450 intrinsic reactivity.