Search Results (366)

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Na_v1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na⁺ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS. Full article

A new series of eight novel etodolac-based 1,3,4-oxadiazoles was synthesized, characterized, and tested in silico in multidimensional routes, starting with etodolac, a well-known nonsteroidal anti-inflammatory medication (NSAID). In silico studies were performed prior to synthesis using the molecular docking technique in CCDC GOLD suite software (2025.3) to assess the interactions with two key targets involved in cancer pathogenesis: the crystal structure of the epidermal growth factor receptor EGFR tyrosine kinase domain (PDB ID: 4HJO) and the matrix metalloproteinase (MMP-9) complex (PDB ID: 5CUH). ADME studies were performed to assess the physicochemical properties of the synthesized molecules. Importantly, biotransformation prediction also indicated that the derivatives possess high metabolic stability, with hydroxylation of the thio-ether group as the primary predicted biotransformation route. All compounds were characterized using melting point, FT-IR, ¹H-NMR, and ¹³C-NMR spectroscopy. In vitro and/or in vivo experiments are needed to confirm this preliminary anticancer study. Full article

Monoterpenes (thymol, carvacrol, menthol) and phenylpropanoids (eugenol and cinnamaldehyde) and their related derivatives are naturally occurring bioactive compounds found in essential oils (EOs) and have attracted considerable interest as anticancer agents; however, their direct therapeutic use in cancer treatment is often limited by factors such as low bioavailability, moderate potency, and lack of target specificity. Recent studies have demonstrated that rational structural modification of these EO scaffolds can substantially enhance their anticancer potential. This review critically evaluates the different structural modification strategies applied to EO components, including pharmacophore hybridization, heterocycle incorporation (e.g., triazoles, oxadiazoles, chalcones), esterification, halogenation, metal complexation, and nanoparticle conjugation. The review compares these approaches across the selected EO components, highlighting their impact on anticancer potency, and mechanistic relevance. However, the current evidence base is heterogeneous, with considerable variability in experimental conditions, selectivity assessments, and reliance on in vitro or in silico findings, which limits direct cross-study comparisons and translational interpretation. Overall, structural modification of EO components represents a promising strategy for generating novel anticancer lead compounds, but future progress will depend on standardized biological evaluation, rigorous in vivo validation, and comprehensive pharmacokinetic and toxicity profiling to realistically define their clinical potential. Full article

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to their diverse pharmacological activities. This study aimed to design, synthesize, and evaluate new hybrid heterocyclic systems, including 1,2,4-triazole, 1,3,4-oxadiazole, and thiadiazine motifs, targeting liver and breast cancer. Methods: A series of indolyl-based heterocyclic compounds was synthesized using efficient and environmentally friendly protocols. Indolyl-triazol-thiadiazin-6-ol 5 was prepared via solvent-free fusion of esters 2 and 3 or the corresponding acid 4. Oxadiazole derivatives were produced by reacting hydrazide intermediates with carbon disulfide. Triazole derivatives were synthesized via cylization of thiosemicarbazide 9 in aqueous KOH (4.0 N). Structural characterization was performed using Fourier Transform InfraRed (FTIR), ¹H and ¹³C NMR spectroscopy, and electron impact mass spectrometry (EIMS). Cytotoxic activity was evaluated against liver and breast cancer cell lines, and VEGFR-2 kinase inhibition was assessed for selected derivatives. Results: The synthesized compounds demonstrated notable cytotoxicity activity, with compounds 4, 5, and 9 exhibiting IC₅₀ values in the low micromolar range. Enzymatic assays revealed that compounds 4 and 9 showed strong VEGFR-2 inhibition (97.9% and 96.4%, respectively), indicating apoptosis-inducing effects. Conclusions: The synthesized indolyl-based hybrid heterocycles represent a promising chemotype with in vitro cytotoxic activity and VEGFR-2 inhibitory effects, supporting further investigation, optimization, and mechanistic studies to evaluate their potential lead for anticancer drug development. Full article

Chronic Obstructive Pulmonary Disease (COPD) is a complex inflammatory lung condition characterized by oxidative stress, changes in airway structure, and gradually worsening airflow blockage. Existing treatments offer only symptomatic management, emphasizing the need for multi-target therapeutic interventions. This study employed a combined approach of network pharmacology and molecular docking to investigate the therapeutic effects of bioactive compounds derived from Cladophora glomerata on COPD. Disease-associated genes were collected from GeneCards, Online Mendelian Inheritance in Man (OMIM), and National Center for Biotechnology Information (NCBI), while compounds from C. glomerata and their predicted molecular targets were obtained from SwissTargetPrediction. A cross-comparison of targets related to compounds and diseases revealed nine common genes, among which three central genes TP53, CASP8, and EGFR were identified using protein–protein interaction (PPI) network analysis. Analysis of gene–disease interactions highlighted Tumor Protein p53 (TP53) and Epidermal Growth Factor Receptor (EGFR) as major regulatory targets. GeneMANIA-based functional and co-expression analysis revealed predominant physical interactions (77.64%) and co-expression relationships (8.01%), highlighting strong functional connectivity among the identified genes. Molecular docking further confirmed that C. glomerata derived compounds, particularly Quinoline, 1,2,3,4-tetrahydro-1-((2-phenylcyclopropyl)sulfonyl)-, trans- (Pubchem ID: 91709903) (−7.5 kcal/mol) and1,2,4-Oxadiazole, 3-(1,3-benzodioxol-5-yl)-5-[(4-iodo-1H-pyrazol-1-yl)methyl]- (Pubchem ID: 5301194) (−7.3 kcal/mol), exhibit favorable predicted binding affinities toward EGFR and TP53 in molecular docking analysis. Overall, these insights suggest that Cladophora glomerata compounds may modulate key COPD-related pathways through multi-target interactions, providing a scientific basis for future experimental studies and the development of marine-derived therapeutic agents for COPD management. Full article

Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the BCR-ABL, among which the T315I substitution constitutes the most clinically significant barrier. Ponatinib effectively inhibits this mutant form but is limited by dose-dependent cardiovascular toxicity, prompting efforts to develop safer and more selective agents. Recent advances highlight aminopyrimidine-derived scaffolds and their evolution into thienopyrimidines, oxadiazoles, and pyrazines with improved activity against BCR-ABL^T315I. Further progress has been achieved with benzothiazole–picolinamide hybrids incorporating a urea-based pharmacophore, which benefit from strategic hinge-region substitutions and phenyl linkers that enhance potency. Parallel research into dual-mechanism inhibitors, including Aurora and p38 kinase modulators, demonstrates additional opportunities for overcoming resistance. Combination strategies, such as vorinostat with ponatinib, provide complementary therapeutic avenues. Natural-product-inspired approaches utilizing fungal metabolites provided structurally diverse scaffolds that could engage sterically constrained mutant kinases. Hybrid molecules derived from approved TKIs, including GNF-7, olverembatinib, and HG-7-85-01, exemplify rational design trends that balance efficacy with improved safety. Molecular modeling continues to deepen understanding of ligand engagement within the T315I-mutated active site, supporting the development of next-generation inhibitors. In this review, we summarized recent progress in the design, optimization, and biological evaluation of small molecules targeting the BCR-ABL^T315I mutation. Full article

The article presents a comprehensive comparative performance evaluation and validation of composite adsorbents based on the Se-derivative of 4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide for U (VI) recovery from complex multicomponent aqueous media. Our results indicate the composite materials to be comparable to, and in some cases to surpass, existing adsorbents in recovery efficiency. Under static sorption conditions for trace U (VI) from real multicomponent solutions (tap, river, and sea water), the sorption efficiency reached 80–98%, while the distribution coefficients ranged from 10⁴ to 10⁶ cm³ g⁻¹. The sorption-selectivity properties of the materials were evaluated in the presence of competing ions (EDTA and oxalate ions), which possess a high chelating capacity and a strong tendency to form complexes with uranium. The dependence of sorption efficiency on the concentration of these ions and the solution pH was investigated. The possibility of reusing the materials over multiple sorption-desorption cycles was assessed. An optimal regenerating eluent agent was identified (NaHCO₃/NH₄NO₃), providing a desorption efficiency of >95% without degrading the material’s sorption properties over repeated cycles. Using a combination of physicochemical methods, including sorption techniques, the mechanism of uranium sorption and its dependence on the material structure were determined. The efficiency of uranium recovery from multicomponent natural waters was also investigated under dynamic conditions over repeated sorption-desorption cycles. The results demonstrate through comparative analysis that the developed composites exhibit a high sorption capacity and possess a high practical potential for the concentration and recovery of uranium from high-salinity solutions with complex composition. Full article

The anti-inflammatory scaffold 5-aminosalicylic acid, which is widely used in therapeutic applications, was chosen for the synthesis of N-[3-(hydrazinecarbonyl)-4-hydroxyphenyl]acetamide (1) to enhance its antibacterial properties. The condensation of hydrazide 1 with aromatic aldehydes provided hydrazone derivatives 2a–f, whereas cyclocondensation reactions and other related transformations afforded five-membered heterocycles, including pyrrole 3, pyrazole 4, pyrrolidinone 7, oxadiazoles 9, 10, thiadiazole 14, and triazole 15. Additional modifications yielded acetylhydrazine derivative 11, which was O-alkylated to analogue 12. Antibacterial evaluation showed stronger activity against Gram-positive bacteria such as S. aureus and MRSA than against Gram-negative strains of E. coli and S. Enteritidis, consistent with differences in cell membrane permeability. Notably, derivatives containing pyrrolidinone 7, thiosemicarbazide 13, and 1,3,4-thiadiazole 14 exhibited potent bactericidal activity against S. aureus and MRSA, while hydrazones 2b, 2c, 2f, pyrrole 3, and pyrrolidinone 7 exhibited activity against E. coli. These results provide a practical strategy for the discovery of heterocyclic compounds and emphasise the potential of functionalised 5-aminosalicylic acid derivatives as prime candidates for the development of broad-spectrum antibacterial agents. Full article

Background/Objectives: Cancer is among the leading causes of mortality worldwide. In 2022 alone, the global cancer death toll stood at 9.74 million. Projections indicate that this figure will rise to 10.4 million by 2025. Methods: A new series of benzimidazolone-bridged hybrid compounds containing thiophene, furan, oxadiazole, piperazine, and coumarin moieties was synthesized and structurally characterized by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis. Their cytotoxic effects were evaluated by MTT assay against human lung (A549), human breast (MCF-7), and human cervical (HeLa) cancer cell lines, and the non-cancerous HEK293 cell line after 48 h exposure over a concentration range of 0.5–250 µM. IC₅₀ values were determined, and Selectivity Indexes (SI) were calculated using HEK293 as the reference normal cell line. Molecular docking studies were carried out using the Glide XP protocol against VEGFR2 (PDB ID: 4ASD) and CDK4–Cyclin D3 (PDB ID: 7SJ3), with sorafenib and abemaciclib as reference inhibitors. Results: The results of anticancer activity were compared with doxorubicin (IC₅₀ ± SD (µM)/SI: 4.3 ± 0.2/1.20 for A549, 6.4 ± 0.37/0.77 for MCF-7, 3.4 ± 0.19/1.54 for HeLa), a drug used for cancer chemotherapy. The structures of the newly synthesized hybrid compounds were identified by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis data. These hybrid compounds represent a promising class of anticancer agents. Several compounds demonstrated marked and concentration-dependent cytotoxicity across all cancer cell lines, with HeLa cells showing the highest overall sensitivity. The introduction of an oxadiazole ring (compound 7) and coumarin substituents (compounds 12b–12d) markedly improved anticancer activity and selectivity, yielding low-micromolar IC₅₀ values in HeLa cells (10.6–13.6 µM) and high Selectivity Indexes (SI = 2.0–3.63). Compound 6 also exhibited balanced potency across A549, MCF-7, and HeLa cells (IC₅₀ = 28.3–31.2 µM) with SI values ≥ 2.0. Compound 9 showed strong cytotoxicity across all cancer cell lines; its moderate SI values indicate lower discrimination between malignant and non-malignant cells. Taken together, these findings identified compounds 7, 12b–12d, 6, and 12c as the most promising benzimidazolone-based candidates, displaying both potent cytotoxicity and favorable selectivity over non-malignant HEK293 cells. Conclusions: Among the synthesized molecules, the oxadiazole derivative (7) and the coumarin-based hybrids (12b–12d) exhibited the strongest combination of cytotoxic activity and selectivity, reflected by their low IC₅₀ values and high SI ratios. Notably, compound 12c combined strong biological activity with the highest predicted VEGFR2 affinity in the series, highlighting it as a particularly promising scaffold. While compound 9 exhibited excellent docking scores toward both VEGFR2 and CDK4, its lower selectivity suggests a need for further structural refinement. Overall, the biological and computational findings converge to identify these benzimidazolone hybrids as credible lead candidates for future anticancer optimization. Full article

Background: Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-associated cancer characterized by dysregulated nitric oxide (NO) signaling and increased NO levels that facilitate tumor progression. Paradoxically, this aberrant NO environment creates a therapeutic vulnerability that can be exploited by NO-donor prodrugs, which overwhelm cellular defenses with cytotoxic concentrations of NO, inducing nitrosative stress and apoptosis. Within this framework, oxadiazole-based scaffolds have emerged as a promising platform for prodrug development owing to their versatile chemistry and potential as novel NO donors or synergistic agents. In our previous studies, we developed several series of hybrid architectures incorporating 1,2,5-oxadiazole 2-oxide (furoxan) and 1,2,4-oxadiazole scaffolds, producing compounds with diverse and tunable NO-donor activities. We further observed that the cytotoxicity of these hybrids was significantly influenced by the substituents introduced at position 3 of the furoxan ring. Methods: We designed and synthesized a series of bis(1,2,4-oxadiazolyl)furoxans to systematically investigate their NO-donating capacity, cytotoxicity against MPM cell lines, selectivity over healthy lung fibroblasts, and underlying anticancer mechanisms. Results: The bis(1,2,4-oxadiazolyl)furoxans exhibited lower overall cytotoxicity but significantly higher selectivity compared with previously studied 3-cyano-4-(1,2,4-oxadiazolyl)furoxans. Their NO-releasing properties showed a strong correlation with their ability to induce mitochondrial damage, as evidenced by membrane depolarization. Moreover, the incorporation of specific substituents, such as a furan ring, on the 1,2,4-oxadiazole moiety introduced an additional mechanism of action through the induction of reactive oxygen species. Conclusions: Analysis of cancer cell death confirmed that these compounds acted through a multimodal mechanism dependent on both NO release and the specific substituents on the 1,2,4-oxadiazole moiety. Full article

In the pursuit of novel anticancer agents, a new series of 1,3,4-thiadiazole derivatives were designed and synthesized, aiming to inhibit tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine implicated in cancer progression. The synthesis involved the initial condensation of substituted anilines with chloroacetic acid to yield 2-(substituted phenylamino)acetic acids, which were then esterified and converted to hydrazides. Cyclization with carbon disulfide and further functionalization produced oxadiazole, thiadiazole, and triazole intermediates. Final thiadiazole-based derivatives (compounds 7a–7d) were obtained by alkylation with substituted phenacyl bromides. These compounds were biologically evaluated for anticancer potential with specific focus on TNF-α inhibition, a critical target in inflammatory and tumorigenic signaling pathways. Molecular docking studies suggested strong binding affinities of the synthesized molecules to the TNF-α active site, indicating their possible role in downregulating pro-inflammatory responses associated with tumor development. Biological screening demonstrated promising cytotoxicity profiles in preliminary in vitro cancer models. Structure–activity relationship (SAR) analysis revealed that electron-withdrawing groups (Cl and F) on the thiadiazole scaffold significantly enhanced TNF-α targeting and anticancer activity. These findings support the potential of these thiadiazole derivatives as promising anticancer agents targeting TNF-α. Full article

Oxadiazoles, nitrogen-containing heterocycles, are attracting interest due to their promising biological activities. This study focuses on the synthesis of oxadiazole derivatives from functionalized intermediates derived from terephthalic acid, a versatile and readily available aromatic precursor widely used for the construction of nitrogen heterocycles and advanced organic structures. Different synthetic approaches were explored to evaluate the feasibility of these processes. Full article

The chemical recycling process of polyethylene terephthalate (PET) was executed through aminolysis employing N, N-Diisopropylethylamine (DIPEA) as the catalytic agent, commencing with the systematic collection and comprehensive purification of discarded PET bottles to remove contaminants and additives. The depolymerization reaction utilized hydrazine as the primary amine source, facilitating the cleavage of ester bonds within the polymer matrix under controlled temperature and pressure conditions. The synthesis of the diamine compound, terephthalohydrazide, was successfully achieved through this catalytic aminolysis pathway, demonstrating high conversion efficiency and product selectivity. The resulting terephthalohydrazide served as a crucial intermediate and was subsequently utilized for the further synthesis of bis-1,3,4-Oxadiazole derivatives through a comprehensive methodology rigorously aligned with the fundamental principles of green chemistry, including atom economy, reduced waste generation, and environmentally benign reaction conditions. A diverse series of six distinct products derived from various carboxylic acids employed in the cyclization synthesis of bis-1,3,4-Oxadiazoles were systematically produced under optimized reaction parameters. These products were meticulously characterized using advanced nuclear magnetic resonance (NMR) spectroscopy techniques, including both ¹H and ¹³C NMR analyses, confirming their structural integrity and chemical composition. This sequential approach represents a significant advancement in heterocyclic synthesis methodology, using sustainable pathways to find structural diversity. Full article

Two heteroaromatic hybrid compounds were synthesized and characterized using various analytical techniques. The results indicate that the benzimidazole/oxadiazole (BZ/OZ) metal derivative exhibits a tridentate coordination mode, where the carbonyl, imidazole and oxadiazole groups participate in coordination with the metal, in a ratio of 2:1 of the ligand to the metal. The antibacterial activities of the organic ligand and its metal complex were determined by in vitro tests against both Gram-positive bacterial strains and Gram-negative bacterial strains using the broth microdilution method. The metal complex showed greater antibacterial activities compared to the precursor ligand against all evaluated microorganisms. The results obtained through in silico predictions revealed significant toxicological differences among the analyzed molecules, suggesting special attention in the use of the ligand due to its possible carcinogenicity in mice and a need for structural modifications in the complex to reduce its carcinogenicity and toxicity. Furthermore, a biophysical study of the interaction of the BZ/OZ derivatives with different model membranes was explored through differential scanning calorimetry (DSC), simultaneous small- and wide-angle X-ray diffraction (SAXD and WAXD) and infrared spectroscopy (FT-IR). The results indicate that the compounds influenced membrane properties without significantly altering the lamellar organization. The findings suggest potential applications in understanding lipid interactions, elucidating toxicology and developing antibacterial agents. Full article

Achieving a balance of good thermal stability, high performance, and appropriate sensitivity in materials remains a primary research goal in energetic materials. In this study, a series of dinitrimine-functionalized tris-1,3,4-oxadiazole-based energetic compounds was synthesized. Dinitroimmine 5 was found to possess favorable thermal stability (T_d = 180 °C), superior mechanical sensitivity (IS = 25 J, FS = 240 N), and good detonation velocity (v_D = 8372 m s⁻¹). These results suggest that this polyheterocyclic backbone structure facilitates the synthesis of high-performance energetic compounds with application potentials. Full article