Search Results (1,752)

A series of carveoylphenol derivatives (1–12) was synthesized using a microwave-assisted approach and evaluated through an integrated in vitro and in silico strategy. Cytotoxicity was assessed against PC-3, MCF-7, and HT-29 human cancer lines, using non-tumorigenic CoN CCD841 cells as a reference. Derivatives 1, 2, 5, 6, 7, 8, and 11 exhibited activity (IC₅₀ < 100 µM) against at least one cancer line, with 2 showing the highest potency (IC₅₀ = 23.2 µM). Flow cytometry of compounds 1, 2, and 5 revealed structure-dependent cellular responses, where 2 at 40 µM induced maximum intracellular ROS generation (39.6%), 1 reduced mitochondrial membrane integrity to 42.1% intact cells, and 5 produced peak caspase activation (34.5%). Molecular docking against caspase-3 yielded predicted binding energies for all three molecules, with 5 scoring −6.4 kcal/mol. SwissADME analysis indicated comparable physicochemical profiles, high predicted gastrointestinal absorption, and potential blood–brain barrier permeability for these three derivatives. Overall, carveoylphenols, particularly compound 2, represent promising scaffolds for further structural optimization and mechanistic investigation. Full article

Giardiasis is a parasitic disease for which there is a growing need to develop new therapeutic alternatives due to the adverse effects associated with first-line treatments such as metronidazole and the increasing emergence of resistant strains. In this study, the in vitro antigiardial activity of three quassinoids, chaparrin (1), amarolide (2), and chaparrinone (3), isolated from the stems of Castela tortuosa Liebm., was evaluated. The compounds were obtained from the methanolic extract through fractionation and chromatographic purification, and their antigiardial activity was determined against Giardia lamblia trophozoites. In addition, in silico studies were conducted to evaluate their physicochemical, pharmacokinetic, and toxicological properties, as well as molecular docking studies against actin, aldose reductase (ARL), and pyruvate: ferredoxin oxidoreductase (PFOR). Chaparrinone (3) exhibited the highest antigiardial activity, with an IC₅₀ 18.98 μg mL⁻¹, whereas chaparrin (1) and amarolide (3) showed lower activity. Amarolide (2) exhibited the highest binding affinities toward the molecular targets, while chaparrin (1) showed the most favorable overall toxicological/ADME profile. Taken together, these findings highlight chaparrinone (3) as a quassinoid of interest for the development of new antigiardial agents and support the need for further enzymatic, pharmacokinetic, and in vivo studies to more precisely determine its therapeutic potential. Full article

Microplastics (MPs) are ubiquitous across environmental compartments and biological systems, yet particle occurrence, ingestion, tissue detection, and trophic transfer are often interpreted as evidence of exposure, bioaccumulation, biomagnification, or ecological risk. We argue that these observations represent distinct stages of the exposure–fate–effect continuum and should not be treated as equivalent. The operational <5-mm definition is useful for monitoring but does not provide a toxicological identity for a heterogeneous particle assemblage. Biologically relevant dose should therefore consider particle-size distribution, morphology, surface properties, and associated chemicals rather than mass or particle number alone. Likewise, organism-associated particles do not necessarily represent internal accumulation, and trophic transfer does not necessarily demonstrate biomagnification. We further argue that BCF, BAF, and BMF are outcome metrics rather than mechanisms and require evidence of particle uptake, distribution, retention, and elimination before they can be meaningfully interpreted. We propose an EGP–BCF–BAF–BMF framework in which the environment-conditioned state of MPs, particularly their mobility and reactivity, provides the upstream context for biological exposure, internal fate, trophic processes, and ecological consequences. Full article

A series of novel quinazolinone-based aldazine and ketazine derivatives (4a–l and 6) was synthesized through the condensation of hydrazine intermediate 2 with substituted aldehydes and isatin using chitosan sulfonic acid (CS–SO₃H) as a recyclable heterogeneous catalyst. The reactions were performed under conventional reflux and solvent-free grinding conditions. The grinding method afforded the target compounds in higher yields (84–90%) within shorter reaction times (21–33 min) using 10 mol% CS–SO₃H at 25 °C. The synthesized compounds were characterized using spectroscopic and elemental analyses. Cytotoxic evaluation against HepG-2 liver carcinoma cells identified compound 4k as the most potent derivative, with an IC₅₀ value of 4.47 ± 0.25 µM. Compounds 4b, 4f, 4h, and 4k exhibited low cytotoxicity toward the non-tumor LLC-MK2 cell line, with IC₅₀ values above 100 µM and selectivity indices of >20.28, >16.00, >16.61, and >22.37, respectively. SAR analysis indicated that heterocyclic substitution, electron-donating groups, and hydrogen-bonding functionalities enhanced cytotoxic activity, whereas bulky aromatic systems and strong electron-withdrawing groups reduced potency. Molecular docking and in silico ADME studies supported the experimental findings and identified compound 4k as a promising candidate for further investigation. Full article

Early insolvency prediction in Small and Medium-sized Enterprises (SMEs) is a critical challenge for financial stability, credit risk management, and public policy-making. Traditional approaches often rely on isolated predictive models that, despite achieving competitive performance, typically lack semantic integration, contextual adaptability, and operational transparency. This paper proposes a cooperative strategy for an Automated Decision-Making (ADM) system that integrates multiple survival analysis methods to estimate insolvency risk over a defined temporal horizon. The system is structured into three functional layers: (i) an input manager responsible for standardizing financial and non-financial indicators; (ii) a multi-model decision core based on heterogeneous survival architectures, whose outputs are harmonized through a semantic integration layer; and (iii) a fuzzy-based Contextual Modulator that calibrates technical risk estimates by modeling regulatory, sectoral, and socioeconomic criteria as fuzzy linguistic variables. This fuzzy logic approach allows the system to capture the inherent uncertainty and structural vulnerability of SMEs, incorporating contextual information beyond strict model-based risk estimates. The architecture is implemented through an interactive interface and incorporates Explainable Artificial Intelligence (XAI) techniques to ensure traceability, enhance interpretability, and facilitate the understanding of model outputs by decision-makers. The results show that the proposed cooperative strategy improves robustness through model cooperation compared with monolithic models and provides dynamic, fuzzy-calibrated risk curves that support contextualized intervention prioritization. This work contributes to the transition from isolated prediction models toward collaborative decision ecosystems aligned with the operational requirements of financial institutions and public policy organizations. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality among women, highlighting the need for further investigation of bioactive compounds with selective effects on cancer cells. This study evaluated the biological effects of the natural coumarin derivative umbelliferone in MCF-7 breast cancer cells using integrated in silico and in vitro approaches. Methods: Molecular docking predicted interactions with AKT1, mTOR, PI3Kα, and Caspase-7, while molecular dynamics simulations and MM/PBSA calculations provided further information on interactions with AKT1 and mTOR. Results: Umbelliferone reduced MCF-7 cell viability in a concentration-dependent manner, with an IC₅₀ of 492 µM after 24 h, whereas 50% viability was not reached in BJ normal fibroblasts up to 1400 µM, corresponding to an IC₅₀ > 1400 µM and a selectivity index > 2.85. Annexin V-FITC/PI analysis showed increased apoptotic populations, with total apoptosis significantly increased at 800 µM. Colony formation analysis further indicated reduced clonogenic capacity. At 400 µM, umbelliferone significantly increased relative Caspase-3/7 and Caspase-9 activities to 1.873 ± 0.635 and 2.483 ± 0.092, respectively, whereas neither activity was significantly increased at 800 µM. In silico ADME analysis predicted properties compatible with commonly used drug-likeness criteria. Conclusions: Collectively, the findings demonstrate effects of umbelliferone on cell viability, apoptosis, clonogenic capacity, and caspase activity in MCF-7 cells, with comparatively lower cytotoxicity toward normal fibroblasts. Computational findings remain hypothesis-generating and do not establish direct target engagement or pathway inhibition. Further mechanistic and in vivo studies are required to determine the biological and pharmacological relevance of these findings. Full article

A new library of benzothiazole–triazole–indazole conjugates (5a–s) was efficiently synthesized via a Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) strategy. The approach involved the preparation of alkynylated indazoles and benzothiazole–azide derivatives, followed by click-chemistry cycloaddition to provide triazole-linked heterocyclic hybrids in good-to-excellent yields (72–95%), demonstrating the robustness of the modular synthetic design. In silico evaluation using SwissADME indicated that several compounds display physicochemical profiles potentially compatible with early-stage hit exploration, although the relatively high TPSA values suggest that membrane permeability may be limited for some derivatives. The antiproliferative activity of conjugates 5a–s was assessed against A2780 (ovarian), A549 (lung), and MDA-MB-231 (breast) cancer cell lines using the MTT assay. Several conjugates exhibited greater in vitro antiproliferative activity toward A2780 cells, with 5r emerging as the most active derivative of the series (IC₅₀ = 15.7 ± 1.6 μM). In addition, 5b showed notable antiproliferative activity against the MDA-MB-231 cell line (IC₅₀ = 10.8 ± 2.9 μM), highlighting cell-line-dependent antiproliferative profiles. Preliminary structure–activity relationship analysis suggested that electronic effects alone do not fully account for the observed antiproliferative activity, and that substituent position, steric factors, and cell-line-dependent factors may also play important roles in modulating biological response. Given the micromolar activity, the MTT-based nature of the assay, and the absence of non-tumoral cell line data, these compounds are best regarded as chemical starting points for further optimization and mechanistic investigation. Full article

Background: Plant-derived natural products are a productive antiviral scaffold source, yet secondary metabolite libraries remain underexplored against HIV-1 amid extensive target-structure redundancy. This study presents a cluster-guided framework for HIV-1 inhibitor prioritization from the KNApSAcK database. Methods: A total of 64,166 SMs were converted to SMILES and queried against BindingDB to identify reported HIV-1 integrase, protease, and reverse-transcriptase associations. A total of 295 HIV-1 protein sequences were aligned and partitioned using DPClusSBO; representative structures (6VDK, 1MUI, 6ELI) per cluster were docked against cluster-mapped SMs using SMINA. Prioritized SMs were evaluated with SwissADME and benchmarked against ChEMBL HIV-1 inhibitors. Results: Clustering resolved three non-overlapping groups (integrase, n = 135; protease, n = 117; reverse transcriptase, n = 42), mapping 285, 124, and 410 SMs, respectively. Predicted docking scores ranged from $-18.91$ to $-4.72$ kcal/mol (integrase), $-26.54$ to $-7.87$ kcal/mol (protease), and $-26.83$ to $-4.59$ kcal/mol (reverse transcriptase). ADME-prioritized reverse-transcriptase compounds scored more favorably than the matched NNRTI reference set (p < 0.001), requiring experimental confirmation of binding affinity. DUD-E enrichment validation showed strong discriminative validity for integrase and protease (ROC-AUC 0.85, 0.78) but not reverse transcriptase (ROC-AUC 0.53), consistent with weaker pose reproduction for the latter. Conclusions: The framework reduced target redundancy and computationally prioritized natural product candidates for HIV-1 as hypothesis-generating predictions requiring experimental validation. Full article

Epidermal growth factor receptor (EGFR) has become one of the most important molecular targets for the development of anticancer agents because of its critical role in regulating cell proliferation, differentiation, and survival. In the present study, a novel series of benzimidazole–triazole derivatives were designed by incorporating pharmacophoric features of clinically used EGFR inhibitors, synthesized, characterized, and evaluated for their anticancer potential. Cytotoxicity studies against the A549 lung cancer cell line identified 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide, 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(hydroxymethyl)acetamide, 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methoxy-N-methylacetamide, and 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide as active derivatives, with compound 5a exhibiting the highest antiproliferative activity (IC₅₀ = 6.014 ± 0.758 µM), and relatively low cytotoxicity toward NIH/3T3 cells. Based on these findings, 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide was further evaluated against EGFR and its clinically relevant mutant forms, EGFR-L858R and EGFR-L858R/T790M. Retrospective in silico ADME analysis indicated that the synthesized compounds generally possessed favorable drug-like properties, with 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide showing the most favorable overall drug-likeness profile among the series. Molecular docking and molecular dynamics studies revealed that compound 2-((4-Ethyl-5-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-6-yl)-4H-1,2,4-triazol-3-yl)thio)-N-methylacetamide formed stable interactions with key residues in the ATP-binding site of unmutated EGFR, supporting the in vitro inhibition results. Overall, synthesized benzimidazole–triazole derivatives may be promising precursor compounds for the development of novel EGFR inhibitors, particularly against unmutated EGFR cancer cells. Full article

Background/Objectives: We examined the association between shear wave elastography (SWE) of the abductor pollicis brevis (APB) and quantitative motor unit potential (MUP) parameters in carpal tunnel syndrome (CTS), using the ulnar-innervated abductor digiti minimi (ADM) as a reference muscle. Methods: In this prospective cross-sectional study, 73 patients with electrodiagnostically confirmed CTS (125 hands) and 37 healthy controls (69 hands) underwent SWE of the median nerve, APB, and ADM. Quantitative MUP analysis of the APB was performed in 65 hands with moderate or severe CTS. Both hands were included and analysed using mixed-effects models with participant as a random intercept; correlations were corrected using the Benjamini–Hochberg procedure. Results: The median nerve cross-sectional area, Young’s modulus, and shear wave velocity were higher in CTS hands than in controls (all p < 0.001), as were APB Young’s modulus (difference 2.85 kPa, 95% CI 0.46 to 5.24; p = 0.020) and shear wave velocity (p = 0.027). The ADM measurements and the within-hand APB/ADM ratio did not differ significantly. APB stiffness did not correlate with any MUP or motor conduction parameter. Weak correlations with sensory distal latency and sensory conduction velocity did not survive correction for multiple comparisons. Conclusions: Increased stiffness of the median nerve and the APB in CTS was not accompanied by a difference in the ulnar-innervated ADM, but the within-hand APB/ADM ratio did not differ either, so anatomical specificity was not established. Increased APB stiffness represented a group-level mechanical change that, in moderate-to-severe CTS, did not track neurogenic motor unit remodelling as measured by needle electromyography, and its clinical role remains to be defined. Full article

Background/Objectives: Blood–brain barrier (BBB) permeability prediction is important for central nervous system drug discovery. Many models rely mainly on chemical structure, omit transport information, and may report optimistic performance when related compounds occur across training and test sets without adequate leakage control. We developed MechBBB, a two-stage, transport-informed machine-learning framework that adds learned efflux, influx, and passive-permeability scores to conventional molecular features and evaluates their added value under explicit leakage control. Methods: In Stage 1, three LightGBM models were trained on separate efflux, influx, and passive-permeability datasets to generate transport-related scores. BBBP compounds were excluded from Stage 1 training by InChIKey matching. In Stage 2, a LightGBM classifier was trained on BBBP using a Murcko scaffold split with the three Stage 1 scores, ten physicochemical descriptors, and 2048-bit ECFP4 fingerprints. Performance was compared with a descriptor-plus-fingerprint baseline without transport scores. External evaluation used a strict B3DB set (n = 4080) with no InChIKey or nonempty scaffold overlap with BBBP and was performed without retraining, recalibration, or threshold adjustment. MechBBB was also compared with official SwissADME BOILED-Egg predictions on a chemically matched external subset. Results: On the BBBP scaffold test set, MechBBB achieved an AUROC of 0.932, an AUPRC of 0.983, an MCC of 0.737, and a balanced accuracy of 0.866. The AUROC improvement over the descriptor-plus-fingerprint baseline was small but statistically significant in the paired test (ΔAUROC = 0.0096; p = 0.0425). Scaffold-grouped cross-validation did not show a consistent ranking advantage from adding the Stage 1 scores. On strict B3DB, MechBBB achieved an AUROC of 0.894 and an AUPRC of 0.893, with no significant ranking advantage over the baseline. On the matched B3DB subset (n = 4043), MechBBB achieved higher accuracy (0.814 vs. 0.682), balanced accuracy (0.806 vs. 0.693), sensitivity (0.910 vs. 0.541), and MCC (0.631 vs. 0.401) than SwissADME BOILED-Egg, whereas BOILED-Egg had higher specificity (0.845 vs. 0.703). SHAP analysis identified TPSA, NumHDonors, and p_pampa among the leading contributors. Conclusions: MechBBB provides a leakage controlled and externally tested framework that combines competitive BBB permeability prediction with per-compound transport-related information. The Stage 1 scores produced a modest internal improvement but did not provide a consistent external ranking advantage, indicating that their main added value is transport-related context rather than a universal increase in predictive accuracy. MechBBB can be used to prioritize compounds for CNS drug discovery before experimental BBB testing and identify compounds that may warrant follow-up studies of passive permeability or active transport. The MechBBB web tool is freely available. Full article

Multifunctional histamine H₃ receptor (H₃R) ligands with cholinesterase inhibitory activity are being explored as potential Alzheimer’s disease therapeutics, but their interactions with biological membranes and associated ADME properties require parallel evaluation. Here, six structurally related alkoxyamine H₃R ligands were characterized using an HPLC-based biomimetic workflow centered on immobilized artificial membrane (IAM) chromatography to assess phospholipid affinity, estimate passive blood–brain barrier permeability and human intestinal absorption. IAM measurements were complemented by HSA/AGP plasma protein binding, biomimetic distribution descriptors, plasma stability, chromatographic lipophilicity at pH 7.4 and solubility in JP1 (pH 1.2), JP2 (pH 6.8), and phosphate buffer (pH 7.4). The IAM models classified all six ligands as CNS-positive and predicted high intestinal absorption, while CHI_IAM values indicated strong membrane affinity. After 24 h, 77.5–89.5% and 62.2–80.5% parent compound remained in human and rat plasma, respectively. Solubility remained measurable across all three media. Integrated consideration of membrane-related ADME properties and previously reported pharmacology prioritized compounds (6), (5) and (2). Compound (6) showed the strongest overall potency–developability balance, although the biomimetic membrane predictions require confirmation in direct permeability, transporter, and in vivo pharmacokinetic studies. Full article

Alzheimer’s disease (DA) remains a major therapeutic challenge, and selective butyrylcholinesterase (BChE) inhibition has emerged as a promising strategy for symptomatic treatment, particularly in advanced stages. Herein, a series of novel quinoline–acylguanidine hybrids was designed through a bioisosteric replacement of acridine–thiosemicarbazones and synthesized via a convergent route combining the Pfitzinger reaction with acylguanidine formation. All derivatives were evaluated against BChE and AChE (acetylcholinesterase), and the 2-phenylquinoline derivative 2c (IC₅₀ = 7.14 µM) was identified as the most potent BChE inhibitor, comparable to donepezil (IC₅₀ = 2.39 µM), with selectivity over AChE. Structure–activity relationships revealed that the 2-phenyl substituent is essential for activity, whereas bulky groups (4-bromophenyl) or replacement with methyl abolished inhibition. Molecular docking showed that active compounds bind within the BChE catalytic anionic site with Trp110, Met465, and Trp458, while inactive analogs undergo a 180° flip of the quinoline scaffold, disrupting key interactions. In silico ADME evaluation indicated a favorable CNS drug-like profile (TPSA < 90 Ų, LogBB > −1, no Lipinski violations, and no predicted P-glycoprotein substrate liability). These findings establish the quinoline–acylguanidine scaffold as a promising new chemotype for the development of selective BChE inhibitors with potential applications in Alzheimer’s disease. Full article

New carbazole-based pyrido[2,3-d]pyrimidine urea and thiourea derivatives (4–6) were synthesized from the previously reported amino intermediate 3, while the previously reported compounds 2 and 3 were included for comparative purposes. The new derivatives were characterized by FT-IR, ¹H NMR, ¹³C NMR, and elemental analysis, and the available spectroscopic and analytical data were evaluated as supporting evidence for their proposed molecular structures. To gain insight into their electronic properties, Density Functional Theory (DFT) calculations were performed at the B3LYP-D3BJ/def2-SVP level of theory. The calculated HOMO–LUMO energy gaps ranged from 2.2711 to 3.3194 eV, revealing noticeable differences in the electronic properties of the investigated derivatives. The fluorophenyl-substituted thiourea derivative 4 exhibited the smallest HOMO–LUMO energy gap together with the highest molecular softness, indicating greater calculated electronic softness, whereas the dichlorophenyl-substituted urea derivative 5 displayed the highest electrophilicity index, indicating the greatest calculated electron-accepting tendency within the series. In contrast, the dichlorophenyl-substituted thiourea derivative 6 exhibited the largest HOMO–LUMO energy gap and the highest calculated hardness. The potential ligand–protein interactions of compounds 2–6 were further investigated by molecular docking against the epidermal growth factor receptor (EGFR, PDB ID: 1M17) and vascular endothelial growth factor receptor-2 (VEGFR-2, PDB ID: 3WZE). Compound 6 yielded the most negative docking scores within the investigated series toward both EGFR (−12.0 kcal/mol) and VEGFR-2 (−12.2 kcal/mol) under the initial docking protocol. The docking procedure was assessed by re-docking the corresponding co-crystallized ligands, with an RMSD of 1.64 Å obtained for EGFR. Additional flexible-receptor and repeated docking analyses against EGFR demonstrated that the minimum docking score was not necessarily the most frequently represented score among the generated poses, supporting consideration of docking-score distributions rather than reliance on a single top-ranked pose. In addition, in silico ADMET analyses using pkCSM and SwissADME revealed model-dependent pharmacokinetic predictions, including contrasting predictions of intestinal/gastrointestinal absorption for derivatives 4–6. Overall, the combined experimental and computational results provide structural characterization and comparative theoretical evaluation of this carbazole-based pyrido[2,3-d]pyrimidine series. The computational findings support further investigation of compounds 4–6; however, experimental biochemical and cellular studies are required to validate the predicted ligand–protein interactions and their biological relevance. Full article

A series of previously synthesized carbazole-based urea and thiourea derivatives (5a–5i) was subjected to an integrated computational investigation of their predicted interactions with epidermal growth factor receptor (EGFR) (PDB ID: 1M17) and their pharmacokinetic and dynamic behavior. Molecular docking yielded scores of −9.0 to −13.5 kcal/mol, with 5f showing the most favorable value (−13.5 kcal/mol). Redocking of the co-crystallized ligand AQ4 yielded an RMSD of 1.65 Å, supporting the docking protocol. SwissADME analysis revealed high lipophilicity, low predicted gastrointestinal absorption, and poor aqueous solubility across the series. Compound 5f showed a Consensus LogP of 7.05, two Lipinski violations, a bioavailability score of 0.17, and predicted P-glycoprotein substrate behavior. SwissTargetPrediction identified EGFR among the predicted targets of 5f, providing complementary computational rationale for its investigation. Three independent 100 ns molecular dynamics simulations of the EGFR–5f complex showed limited protein backbone deviations (mean RMSD: 0.217–0.282 nm), maintained overall compactness (mean Rg: 2.005–2.040 nm), and continued protein–ligand association despite replicate-dependent conformational sampling. Overall, 5f was computationally prioritized based on its favorable predicted EGFR interactions and sustained association over the investigated simulation timescale, while its physicochemical and pharmacokinetic limitations indicate the need for further structural optimization and experimental validation. Full article