Search Results (128)

Background: Oral squamous cell carcinoma (OSCC) is an aggressive cancer closely associated with smoking and alcohol consumption, with a higher incidence in men. Despite changes in treatment strategies, poor survival persists in most patients, highlighting the need for novel and improved therapeutic options. Naphthoquinone analogs are being investigated because of their active redox structure and broad pharmacological profile; they demonstrate cytotoxic antitumor activity, making them potential candidates for new drug agents. Objective: This study investigated new benzyl-naphthoquinone compounds as potential anticancer agents for various genotypes of oral squamous cell carcinoma (OSCC) and other cancer cells. Methods: This study reports the synthesis and evaluation of a series of eight benzyl-naphthoquinone compounds against oral squamous cell carcinoma. Results: Four compounds 1–4 showed the best cytotoxic profiles, with a selectivity index ≥ 3 for all OSCC cell lines tested. Compound 1 was the most selective compound in all OSCC models, showing a higher selectivity index than both carboplatin and shikonin. Furthermore, compound 1 induced DNA fragmentation, cell-cycle arrest, and caspase-3/7 activation, changes consistent with apoptosis, and time-lapse imaging corroborated the apoptotic phenotype. Hemolysis assays showed minimal toxicity in human erythrocytes, and acute in vivo evaluation in mice revealed no evident adverse effects under the conditions tested, indicating low acute toxicity, although more detailed histopathological and biochemical studies will be required to fully establish the safety profile. Molecular modeling suggested that compound 1 may interact with topoisomerase II, RSK2, and PKM2, which could contribute to the activation of apoptotic pathways, although these interactions remain predictive and require biochemical validation. Finally, in silico analysis of physicochemical and ADMET parameters indicated properties compatible with oral absorption and systemic exposure, together with predicted low toxicity; however, these results are model-based and should be confirmed experimentally. Conclusions: Based on these findings, compound 1 emerges as a promising lead candidate for the development of a novel chemotherapeutic agent against OSCC, with potential therapeutic efficacy against other cancer types. Full article

Background: Antiviral therapies are widely used during pregnancy and are generally considered safe, pregnancy-specific severe safety signals continue to be observed in post-marketing pharmacovigilance data. These signals are rarely interpreted within an integrated mechanistic framework. Methods: We analysed pregnancy-related EudraVigilance reports (2015–2025) using a previously network-based pharmacovigilance framework. Established ADR clusters were treated as fixed phenotypes and integrated with in silico ADMET liabilities, literature-derived pregnancy pharmacokinetic/pharmacodynamic (PK/PD) parameters, polypharmacy and co-medication network metrics, and exploratory statistical, machine-learning, and exposure–liability analyses for mechanistic prioritisation. Results: Phenotype membership explained 22.3% of the variance in composite ADMET risk (intraclass correlation coefficient = 0.223; p < 0.001), and all tested ADMET parameters differed significantly across phenotypes (FDR-adjusted p < 10⁻¹⁰). One phenotype showed pronounced enrichment, with 13 antivirals over-represented. Polypharmacy strongly modified seriousness, with odds of serious outcomes increasing by ~5% per additional co-reported active drug (OR 1.05, 95% CI 1.04–1.05). A composite mechanistic vulnerability index showed moderate concordance with empirical burden (Spearman’s ρ = 0.65), while regimen-level prioritisation of drug–drug interactions (DDIs) identified no high-priority combinations. Conclusions: Pregnancy-related antiviral ADRs cluster into reproducible phenotypes driven by mechanistic liability and system-level complexity, supporting mechanistically informed prioritisation and targeted pharmacometric follow-up. Full article

Background: Oils from medicinal plants, including thyme (Thymus vulgaris), cinnamon (Cinnamomum verum), and black seed (Nigella sativa), are recognized for their antibacterial and antioxidant properties. While several studies have investigated individual oils and binary combinations, fewer reports have examined ternary mixtures using systematic optimization approaches. Accordingly, the present study aimed to optimize the antibacterial and antioxidant performance of combinations of these three plant-derived oils using a statistical mixture design strategy supported by in silico exploration. Methods: An Augmented Simplex Centroid Mixture Design was applied to evaluate the individual and combined effects of thyme, cinnamon, and black seed oils. Antibacterial activity was assessed by determining the minimum inhibitory concentrations (MICs) against Escherichia coli and Staphylococcus aureus, while antioxidant activity was measured using the DPPH radical scavenging assay (IC₅₀). The experimental data were fitted to a special cubic model, and model validity was verified through ANOVA parameters, including F-values, R², and adjusted R². Multi-response optimization was performed using a desirability function. Potential interactions among oils were further examined using checkerboard assays. Molecular docking and ADMET predictions were conducted as supportive, hypothesis-generating tools. Results: The special cubic model was statistically significant for all responses (p < 0.0001), with R² values of 0.9763, 0.9944, and 0.9841 for MIC_{E. coli}, MIC_{S. aureus}, and DPPH IC₅₀, respectively. Response surface analysis and multi-response optimization identified the optimal oil mixture as thyme (41.7%), cinnamon (41.7%), and black seed (16.7%), achieving MIC values of 0.5 µL/mL for E. coli and 0.517 µL/mL for S. aureus, and a DPPH IC₅₀ of 5.32 ± 0.52 mg/mL. Checkerboard assays confirmed synergistic interactions for the optimized formulation, with ΣFIC values of 0.15 and 0.29 against E. coli and S. aureus, respectively. Cytotoxicity testing of the optimized formulation on WI-38 normal fibroblasts indicated high cell viability (>92%) at all tested concentrations. In silico docking showed favorable binding affinities of major oil constituents with bacterial targets, and ADMET analysis suggested acceptable pharmacokinetic and safety profiles. Conclusions: The study demonstrated that specific combinations of thyme, cinnamon, and black seed oils can synergistically enhance antibacterial and antioxidant activities. The optimized formulation exhibited enhanced antibacterial and antioxidant activities with minimal cytotoxicity, while in silico analyses provided supportive mechanistic insights. Full article

Kratom (Mitragyna speciosa (Korth.) Havil.) oxindole alkaloids remain underexplored compared to the well-studied indole constituents mitragynine and 7-hydroxymitragynine. Previous research has primarily focused on phytochemical identification and preliminary pharmacology, with limited pharmacokinetic insight. This study pioneers an in silico ADMET modeling analysis of 27 kratom-derived oxindole alkaloids using ADMET Predictor™ v3.0, delivering the first comprehensive predictions of their physicochemical properties, CYP450/UGT enzyme interactions, transporter affinities, permeability, and pharmacokinetic parameters. Representative compounds such as speciophylline, isomitraphylline, and isospeciophylline displayed notably favorable predicted jejunal permeability and moderate metabolic stability, suggesting promising oral drug-like characteristics. Across the dataset, high CYP3A4 substrate affinity (98% confidence), variable CYP3A4, CYP2D6, CYP2C19 inhibition, strong P-gp substrate potential, and differential BBB penetration probabilities (46–99%) were observed. These findings provide a foundational computational framework to guide future experimental validation and rational drug development of kratom oxindole alkaloids. Full article

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol’s reliability. Results: The top compounds—H7, H10 and H11—showed potent cruzain inhibition (IC₅₀ = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC₅₀ > 64 µM) and favorable selectivity. Structure–activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1′ subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. Conclusions: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain. Full article

Kratom alkaloids are classified as aromatic pentacyclic indole and substituted carbonyl oxindole alkaloids. This study investigates the metabolism and interactions of indole alkaloids using in silico tools, including ADMET Predictor 13.0™, to assess pharmacokinetic and metabolic profiles. The analysis examined absorption, distribution, metabolism, and excretion (ADME), focusing on cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzyme interactions, drug transporters, and clearance. Most indole alkaloids showed strong substrate interaction and inhibition of CYP3A4 (79–99% confidence) and induction of CYP1A2 (up to 94% confidence). Among UGT enzymes, UGT1A1 demonstrated the highest substrate affinity (97%), while none interacted with UGT2B15. All alkaloids showed strong P-glycoprotein (Pgp) interaction but minimal inhibition of BCRP. Mitralactonine exhibited the highest skin permeability, and Mitralactonal showed maximal jejunal permeability. Most indole alkaloids demonstrated significant blood–brain barrier penetration (up to 99% confidence) and compliance with Lipinski’s rule of five. Predictive modeling indicated notable effects on hepatic microsomal clearance parameters. This investigation offers the first comprehensive in silico ADMET profiling of kratom indole alkaloids, uncovering their CYP3A4 inhibition potential and metabolic liabilities to prioritize candidates for safer therapeutic development, though limited by model biases, applicability domain restrictions, and inability to fully capture biological complexity, stereochemistry, or interindividual variability necessitating experimental in vitro and in vivo validation. Full article

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a central therapeutic target in Alzheimer’s disease, as it catalyzes the rate-limiting step in amyloid-β production. Verubecestat (VER), a clinical BACE1 inhibitor, failed in late-stage trials due to limited efficacy and safety concerns. This study employed an integrative computational approach to design VER derivatives with improved binding affinity, stability, and pharmacokinetic profiles. Structural similarity analysis, Molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, 200 ns molecular dynamics (MD) simulations, MM/PBSA free energy calculations, and per-residue decomposition were performed. In silico ADMET profiling assessed drug-likeness, absorption, and safety parameters. Docking and pharmacophore analyses identified derivatives with stronger complementarity in the BACE1 catalytic pocket. MD simulations revealed that VERMOD-33 and VERMOD-57 maintained low root mean square deviations (RMSDs) and stable binding orientations and induced characteristic flexibility in the flap and catalytic loops surrounding the catalytic dyad (Asp93 and Asp289), consistent with inhibitory activity. MM/PBSA confirmed the superior binding free energies of VERMOD-33 (−51.12 kcal/mol) and VERMOD-57 (−43.85 kcal/mol), both outperforming native VER (−35.33 kcal/mol). Per-residue decomposition highlighted Asp93, Asp289, and adjacent flap residues as major energetic contributors. ADMET predictions indicated improved oral absorption, BBB penetration, and no mutagenicity or toxicity alerts. Rationally designed VER derivatives, particularly VERMOD-33 and VERMOD-57, displayed enhanced binding energetics, stable inhibitory dynamics, and favorable pharmacokinetic properties compared with native VER. These findings provide a computational framework for rescuing VER and support further synthesis and experimental validation of next-generation BACE1 inhibitors for Alzheimer’s disease. Full article

Serotonin receptors, in particular 5-HT_1A and 5-HT_2A receptors, are important molecular targets for the central nervous system (CNS) disorders, such as schizophrenia, depression, anxiety disorders, memory deficits, and many others. Here, we present structural and pharmacological evaluation of a serotonin receptor ligand, SERAAK2, identified in a structure-based virtual screening campaign. Molecular docking studies revealed that SERAAK2 binds with its molecular targets via Asp3.32 as the main anchoring point, which is typical for orthosteric ligands of aminergic GPCRs. Molecular dynamics simulations confirmed the stability of the ligand binding poses in the studied receptors. MMGBSA calculations were in accordance with the receptor in vitro binding affinity studies, which indicated that SERAAK2 is a potent ligand of 5-HT_1A and 5-HT_2A receptors. It was also found that SERAAK2 displays favorable ADMET parameters. The demonstrated anxiolytic- and antidepressant-like effects of SERAAK2 in animal models, which may involve its interaction with 5-HT_1A receptors, warrant further studies to confirm these activities and elucidate the underlying mechanisms. Full article

Background/Objectives: Vector-borne diseases like malaria remain a major global health concern, worsened by insecticide resistance in mosquito populations. Quinoline-based compounds have been extensively studied for their pharmacological effects, including antimalarial and larvicidal properties. Modifying quinoline structures with hydrazone groups may enhance their biological activity and physicochemical properties. This study reports the synthesis, structural characterization, and larvicidal testing of a new series of aryl hydrazones (6a–i) derived from 8-trifluoromethyl quinoline. Methods: Compounds 6a–i were prepared via condensation reactions and characterized using ¹H NMR, ¹⁹F-NMR, ¹³C NMR, and HRMS techniques. Their larvicidal activity was tested against Anopheles arabiensis. Single-crystal X-ray diffraction (XRD) was performed on compound 6d to determine its three-dimensional structure. Hirshfeld surface analysis, fingerprint plots, and interaction energy calculations (HF/3-21G) were used to examine intermolecular interactions. Quantum chemical parameters were computed using density functional theory (DFT). Molecular docking studies were performed for the synthesized compounds 6a–i against the target acetylcholinesterase from the malaria vector (6ARY). In silico ADMET properties were also calculated to evaluate the drug-likeness of all the tested compounds. Results: Compound 6a showed the highest larvicidal activity, causing significant mortality in Anopheles arabiensis larvae. Single-crystal XRD analysis of 6d revealed a monoclinic crystal system with space group P2₁/c, stabilized by N–H···N intermolecular hydrogen bonds. Hirshfeld analysis identified H···H (22.0%) and C···H (12.1%) interactions as key contributors to molecular packing. Density functional theory results indicated a favorable HOMO–LUMO energy gap, supporting molecular stability and good electronic distribution. The most active compounds, 6a and 6d, also showed strong binding interactions with the target protein 6ARY and satisfactory ADMET properties. The BOILED-Egg model is a powerful tool for predicting both blood–brain barrier (BBB) and gastrointestinal permeation by calculating the lipophilicity and polarity of the reported compounds 6a–i. Conclusions: The synthesized arylhydrazone derivatives demonstrated promising larvicidal activity. Combined crystallographic and computational studies support their structural stability and suitability for further development as eco-friendly bioactive agents in malaria vector control. Full article

Imidazolium-based ionic liquids bearing a homologous series of oxychlorine anions—1-butyl-3-methylimidazolium chlorite, chlorate, and perchlorate—were synthesized and characterized to relate anion oxygenation to density, thermal expansivity, viscosity, electrical and molar conductivity, ionicity, and antimicrobial performance. Temperature-dependent measurements were carried out from 293.15 to 323.15 K: density and viscosity were recorded and modeled to obtain thermal expansion coefficients; electrical and molar conductivities were measured under identical conditions; and activation parameters were extracted by Arrhenius analysis for viscous flow and for conductivity. Ionicity was assessed from Walden plots and quantified by vertical deviation from the potassium-chloride reference (Angell approach). Complementary DFT calculations provided optimized ion-pair geometries, noncovalent contact patterns, molecular electrostatic potential maps, and frontier-orbital descriptors. In silico ADMET properties were computed to contextualize pharmacokinetic and safety flags. Antimicrobial activity was evaluated by broth microdilution against Escherichia coli, Staphylococcus aureus, Bacillus cereus, and Candida quilliermondii; [Bmim]Cl was included as a comparator to isolate the effect of anion oxygenation. The combined experimental–computational workflow delineates how chlorite, chlorate, and perchlorate shape physicochemical behavior, ionicity, and bioactivity in [Bmim] ionic liquids, providing design guidance for future applications. Full article

Although traditionally contraindicated, the coadministration of tamoxifen and estradiol may hold clinical relevance in specific contexts, particularly in breast cancer survivors with premature menopause and a high risk of osteoporosis, thereby justifying the need to re-evaluate this therapeutic combination. This study presents an innovative physiologically based pharmacokinetic (PBPK) modeling approach to evaluate the coadministration of tamoxifen and estradiol in women with breast cancer and a high risk of osteoporosis. Using GastroPlus^® software, PBPK models were developed and validated for both drugs, based on physicochemical and kinetic data obtained from the literature and, where necessary, supplemented by estimates generated in ADMET Predictor^®. The simulations considered different hormonal profiles (pre and postmenopausal) and therapeutic regimens, evaluating potential interactions mediated by the CYP3A4 enzyme. Analysis of the pharmacokinetic parameters (F, C_max, T_max and AUC) revealed strong agreement between the simulated and experimental values, with prediction errors of less than twofold. The drug interaction studies, carried out in dynamic and stationary modes, indicated that estradiol does not significantly alter the pharmacokinetics of tamoxifen, even at increasing doses or in enlarged virtual populations. These results represent the first in silico evidence that, under certain conditions, the concomitant use of estradiol does not compromise the pharmacokinetic efficacy of tamoxifen. Although the study is computational, it provides a solid scientific basis for re-evaluating this therapeutic combination and proposes a pioneering model for personalized strategies in complex oncological contexts. All simulations assumed average enzyme abundance/activity without CYP polymorphism parameterization; findings are restricted to parent-tamoxifen pharmacokinetics and do not infer metabolite (e.g., endoxifen) exposure or phenotype effects. Full article

Background/Objectives: The increasing prevalence of multidrug-resistant Staphylococcus aureus represents a major clinical challenge, primarily driven by the acquisition of multiple resistance mechanisms. Among these, efflux pumps such as NorA play a pivotal role in quinolone resistance by promoting active drug extrusion and reducing intracellular antibiotic levels. This study evaluated the synthetic chalcone CMA4DMA as a potential NorA efflux pump inhibitor and modulator of bacterial resistance. Methods: Antimicrobial susceptibility assays were conducted against S. aureus SA1199 (wild-type) and SA1199B (NorA-overexpressing) strains. The minimum inhibitory concentration (MIC) of CMA4DMA and its modulatory effects on norfloxacin and ethidium bromide were determined. Efflux inhibition was assessed by ethidium bromide accumulation and SYTOX Green assays. Molecular docking and in silico ADMET analyses were performed to predict binding affinity and pharmacokinetic parameters. Results: CMA4DMA exhibited no intrinsic antibacterial activity (MIC ≥ 1024 µg/mL) but reduced the MIC of norfloxacin from 32 to 8 µg/mL and that of ethidium bromide from 32 to 8 µg/mL in SA1199. In SA1199B, reductions from 64 to 16 µg/mL and from 64 to 32 µg/mL were observed, respectively. Fluorescence increased by 15% without affecting membrane integrity. Docking revealed a binding affinity of −7.504 kcal/mol, stronger than norfloxacin (−7.242 kcal/mol), involving key residues Leu218, Ile309, Arg310, and Ile313. ADMET data indicated high intestinal absorption (88.76%) and permeability (Papp = 1.38 × 10⁻⁵ cm/s). Conclusions: CMA4DMA effectively restored norfloxacin susceptibility in resistant S. aureus strains, highlighting its potential as a promising scaffold for developing novel efflux pump inhibitors and antibiotic adjuvants. Full article

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus. Full article

The aim of this work was to prepare new heterodimeric molecules containing pharmacophoric fragments of 3-cyanoquinoline/3-aminothieno[2,3-b]pyridine/3-aminothieno[2,3-b]quinoline on one side and phenothiazine on the other. The products were synthesized via selective S-alkylation of readily available 2-thioxo-3-cyanopyridines or -quinolines with N-(chloroacetyl)phenothiazines, followed by base-promoted Thorpe–Ziegler isomerization of the resulting N-[(3-cyanopyridin-2-ylthio)acetyl]phenothiazines. We found that both the S-alkylation and the Thorpe–Ziegler cyclization reactions, when conducted with KOH under heating, were accompanied to a significant extent by a side reaction involving the elimination of phenothiazine. Optimization of the conditions (0–5 °C, anhydrous N,N-dimethylacetamide and NaH or t-BuONa as non-nucleophilic bases) minimized the side reaction and increased the yields of the target heterodimers. The structures of the products were confirmed by IR spectroscopy, ¹H, and ¹³C DEPTQ NMR studies. It was demonstrated that the synthesized 3-aminothieno[2,3-b]pyridines can be acylated with chloroacetyl chloride in hot chloroform. The resulting chloroacetamide derivative reacts with potassium thiocyanate in DMF to form the corresponding 2-iminothiazolidin-4-one; in this process, phenothiazine elimination does not occur, and the Gruner–Gewald rearrangement product was not observed. The structural features and spectral characteristics of the synthesized 2-iminothiazolidin-4-one derivative were investigated by quantum chemical methods at the B3LYP-D4/def2-TZVP level. A range of drug-relevant properties was also evaluated using in silico methods, and ADMET parameters were calculated. A molecular docking study identified a number of potential protein targets for the new heterodimers, indicating the promise of these compounds for the development of novel antitumor agents. Full article

Background: Dental caries arise from polymicrobial biofilms and require interventions that address both local virulence and systemic burden. Methods: A curated set of 124 neem-derived phytochemicals was screened against Streptococcus mutans glucansucrase (3AIC) and Staphylococcus aureus DNA gyrase B (3U2D) using harmonized AutoDock Vina parameters. Ligand standardization and receptor preparation followed conventional protocols. Results: The most favorable docking scores reached −10.7 kcal·mol⁻¹ for 3AIC and −8.9 kcal·mol⁻¹ for 3U2D. Redocking produced pose RMSD values of 1.52 Å (3AIC) and 0.96 Å (3U2D). Per-receptor ADMET profiles for the six top-ranked compounds indicated median logP values of 4.93 (3AIC) and 4.52 (3U2D), median TPSA values of 80.3 and 62.9 Ų, median rotatable bonds of 2.5 and 1.0, and median QED values of 0.41 and 0.76, respectively. Conclusions: An integrated, dual-target screen prioritized neem constituents with plausible local anti-cariogenic activity and physicochemical features compatible with systemic disposition. These in silico findings motivate targeted experimental validation. Full article