Search Results (565)

Introduction: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults, with poor prognosis due to relapse, metastasis, and chemoresistance. The search for novel metal-based therapeutics has highlighted copper complexes as promising candidates. Here, we report the in vitro and in vivo antitumor activity of a tetranuclear Cu(II)-hydrazone complex (Cu₄L₄) derived from (E)-5-chloro-N′-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide. Results: Cytotoxic assays on MG-63 OS cells revealed potent activity with an IC₅₀ of 0.50 ± 0.04 µM, significantly surpassing its free ligand (IC₅₀ = 13.9 ± 1.6 µM) and cisplatin (IC₅₀ = 39.0 ± 1.8 µM). This tetranuclear complex outperforms mononuclear Cu-hydrazones analogs (e.g., 4-fold vs. CuHL1, 2-fold vs. CuHL2, 5-fold vs. CuHL3, 17-fold vs. CuHL4,), and Cu₄L₄ also exhibits reduced clonogenic survival, induces reactive oxygen species production, and promotes late apoptosis as a main mechanism, being the main mechanism of action involved in anticancer activity. In multicellular tumor spheroids, the complex maintained strong cytotoxicity (IC₅₀ = 4.11 ± 0.12 µM), impaired spheroid integrity, and markedly inhibited cell migration at sub-IC₅₀ concentrations. The tetranuclear architecture confers markedly enhanced antitumor activity relative to the corresponding mononuclear Cu–hydrazone complexes (e.g., 2-fold vs. CuHL1, 4-fold vs. CuHL2, 2-fold vs. CuHL3). In a xenograft model, sustained administration of Cu₄L₄ (2 mg/kg, i.p., twice weekly) inhibited tumor growth by 43.6%, reduced mitotic index, and increased necrotic area without significant systemic toxicity. Conclusions: Overall, Cu₄L₄ displayed potent and selective antitumor activity against OS cells in 2D, 3D, and in vivo models, underscoring copper–hydrazone complexes as promising scaffolds for the development of new therapies against OS. Full article

Leishmaniasis is a global health issue, especially in tropical and subtropical areas, with treatment challenges due to the development of resistance to current drugs. This has prompted the search for new antileishmanial compounds. Endoperoxides, due to parasites’ reliance on external iron and susceptibility to oxidative stress, are promising antileishmanial compounds. This study evaluated two sterol endoperoxides—ergosterol endoperoxide (ErgoEP) and dehydrocholesterol endoperoxide (DHCholEP)—for their antileishmanial activity and mechanism in vitro. Cell viability assays with Leishmania donovani and Leishmania tarentolae promastigotes showed IC₅₀ values in the low micromolar range (from 2.0 to 4.5 µM, respectively) with low toxicity to murine and J774A.1 macrophages. Electron paramagnetic resonance spectroscopy confirmed radical generation in the presence of low-molecular-weight iron compounds. However, this did not trigger the antileishmanial effect, as neither N-acetylcysteine nor pyridoxal isonicotinoyl hydrazone altered activity. Mitochondrial function(s) and superoxide production in Leishmania remained unaffected. Both endoperoxides significantly inhibited synthesis of 5-dehydroepisterol, the major sterol in Leishmania tarentolae, suggesting targeting of the sterol biosynthesis pathway. Their limited toxicity to mammalian macrophages makes ergosterol and dehydrocholesterol endoperoxides promising candidates for future antileishmanial drug development. Full article

Background/Objectives: Adenine derivatives are promising anticancer scaffolds, but their cellular mechanisms remain unclear. This study aimed to synthesize adenine–hydrazone hybrids and evaluate their cytotoxic effects in human lung adenocarcinoma (A549) cells. Methods: A series of adenine–hydrazone compounds (3a–r) was synthesized and tested for cytotoxicity in A549 and MRC-5 cells. Selected compounds were further analyzed for LDH release, oxidative stress markers, ROS production, mitochondrial membrane potential, cell-cycle distribution, apoptosis, and in silico docking against VEGFR2, ALK5, and EGFR. Results: Compounds with electron-withdrawing or donor–acceptor substituents showed the highest cytotoxicity, while halogenated and methoxy analogs were moderately active. Among the synthesized derivatives, 4F-substituted derivatives (3c) showed more activity than 2F- and 3F-substituted ones (3a and 3b). 4F- and 3Br-substituted derivatives (3f) showed more activity than only 4F-substituted ones (3c). 4-Nitro-substituted derivative (3i) showed more activity than 4F- (3c), 4Cl- (3d) and 4OMe- (3h) derivatives. Trimethoxy-substituted derivative (3l) showed more activity than di- and mono-substituted methoxy derivatives (3g, 3h, 3j and 3k). Among the salicyl aldehydederivatives (3m–r), 4-N(et)₂-substituted derivative (3r) showed more activity than non-substituted (3m), 5Br-(3n), 5Cl-(3o), 5Me (3p) and 3OCH₃ (3q) derivatives. Treatment induced oxidative stress, mitochondrial depolarization, Sub-G1 cell-cycle accumulation, and apoptosis. Docking studies indicated strong binding to VEGFR2 and ALK5, suggesting dual inhibition as a potential mechanism. Conclusions: Adenine–hydrazone derivatives exert substituent-dependent anticancer effects by inducing redox imbalance-associated mitochondrial dysfunction and regulated cell death. These results highlight their potential as lead structures for lung cancer therapy. Full article

Background/Objectives: Hydrazones are organic compounds with the general structure R₂C=NNHR₁, distinguished by their versatility and modifiability, and are widely used in various applications due to their physicochemical and biological properties. They exhibit anticancer, anti-inflammatory, antibiofilm, and antibacterial activities. Antibiotic-resistant bacteria pose a serious public health threat, employing mechanisms such as enzymatic inactivation and efflux pumps. This study evaluated the antibacterial activity of the hydrazone HDZH1,4BENZ, a hydralazine-derived compound, as well as its potential adjuvant effect in combination with antibiotics against Staphylococcus aureus strains expressing efflux pumps. Methods: The strains used were 1199B (NorA efflux pump-expressing) and K2068 (MepA efflux pump-expressing). All assays were conducted using the broth microdilution method in Brain Heart Infusion (BHI) medium. Initially, the intrinsic antibacterial activity of the compound was determined. Subsequently, modulation assays were performed to evaluate its potential effect on efflux pump activity, with a standard efflux pump inhibitor included as a positive control. Results: Although HDZH1,4BENZ did not demonstrate significant direct antibacterial activity, the results indicate that this hydrazone exerts a notable inhibitory effect on the NorA (Norfloxacin resistance efflux pump A) and MepA (Multidrug efflux protein A) efflux pumps in S. aureus, thereby enhancing the efficacy of antibacterial agents. Conclusions: The activity of the hydrazone was comparable to that of chlorpromazine, suggesting that it may represent a promising alternative in the fight against antibiotic-resistant bacterial infections. Full article

Objectives: This study developed pH/enzyme-sensitive polymeric HA-AAN-DOX (HAD) micelles to resolve the limited targeting specificity of chemotherapy drugs. Methods: Hyaluronic acid (HA) and the chemotherapeutic agent doxorubicin (DOX) were conjugated via a hydrazone linkage utilizing an Ala-Ala-ASP tripeptide (AAN) as the connecting moiety, which is sensitive to the legumain enzyme. DOX was delivered via HAD micelles, which were activated by both hyaluronidase and the legumain enzyme. Key findings: The results revealed the remarkable antitumor efficacy of these micelles both in vivo and in vitro. Compared with that of doxorubicin hydrochloride (DOX·HCl), the incidence of toxic side effects was significantly reduced with the HAD micelle treatment. As a result, micelles composed of hyaluronic acid and doxorubicin (HAD) offer a reliable and effective method for drug delivery, with the potential to optimize the therapeutic impact of chemotherapeutic agents on tumors by reducing unintended side effects. Conclusions: Micelles composed of hyaluronic acid and doxorubicin (HAD) offer a reliable and effective method for drug delivery, with the potential to optimize the therapeutic impact of chemotherapeutic agents on tumors by reducing unintended side effects. Full article

Background/Objectives: The development of novel small-molecule kinase inhibitors remains an important strategy in anticancer drug discovery. Receptor tyrosine kinases such as c-MET and HER2 are clinically relevant targets involved in tumor progression and resistance mechanisms. The aim of this study was to design, synthesize, and biologically evaluate a series of 3-[(2,4-difluorophenyl)amino]propanoic acid derivatives as potential antiproliferative agents and to explore their possible interactions with selected kinase targets. Methods: A series of ester, hydrazide, hydrazone, semicarbazide, triazolone, and triazolethione derivatives (2–21) were synthesized and structurally characterized by NMR, IR spectroscopy, and microanalysis. The compounds were evaluated for in vitro anticancer activity against A549 and Caco-2 human cancer cell lines. In addition, molecular docking studies were performed to investigate binding interactions with c-MET and HER2 receptor tyrosine kinases. Cytotoxicity toward non-transformed HEK293 cells was also assessed. Results: The synthesized derivatives demonstrated structure–activity relationships, with compounds 6b, 7f, 7g, and 9 exhibiting the most pronounced antiproliferative effects, reducing cancer cell viability by approximately 50% in both tested cell lines. Molecular docking indicated that compound 9 displayed favorable predicted binding energies toward c-MET and HER2, forming hydrophobic and hydrogen-bond interactions within the active sites and showing overlapping contacts with native ligands and reference inhibitors. Active compounds also demonstrated cytotoxic effects in HEK293 cells comparable to those of doxorubicin and cisplatin. Conclusions: These results identify 3-[(2,4-difluorophenyl)amino]propanoic acid derivatives, particularly compound 9, as promising scaffolds for further structural optimization toward the development of kinase-targeting antiproliferative agents. Full article

Background: Indole-3-acetic acid (IAA)-based hydrazone derivatives, exemplified by specifically (E)-2-(1H-indol-3-yl)-N′-(3-methoxybenzylidene) acetohydrazide acetohydrazide (MBIH) and (E)-N′-(4-fluorobenzylidene)-2-(1H-indol-3-yl) acetohydrazide (FBIH), have garnered significant attention in the field of heavy metal toxicity for their potent antioxidant and cytoprotective properties. Methods: This study evaluated their efficacy, alongside ascorbic acid (AA), in mitigating sub-chronic cadmium (Cd) toxicity in a rat model. Sixty Swiss albino rats were randomized into five groups: control, Cd-exposed, Cd + AA (100 mg/kg), Cd + MBIH (10 mg/kg), and Cd + FBIH (10 mg/kg). Following 28 days of treatment, we assessed body weight trajectories, fasting blood glucose, and HbA1c. Serum biomarkers of hepatic, renal, inflammatory, and lipid function were quantified. Antioxidant capacity was measured via glutathione (GSH) assays and qRT-PCR analysis of SOD2, CAT, Nrf2, and Hmox 1 expression. Untargeted LC–MS/MS metabolomic profiling of serum identified disturbances in amino acids and lipid species, while histopathology of brain, liver, and pancreas documented structural injury. Results: Cd exposure induced significant weight loss, hyperglycemia, and elevated HbA1c, alongside dyslipidemia and heightened inflammatory markers. Hepatic and renal dysfunction, GSH depletion, and downregulation of antioxidant genes confirmed oxidative stress. Metabolomics revealed a Cd-specific fingerprint characterized by altered sulfur amino acid and phospholipid metabolism. Histologically, Cd caused liquefactive necrosis in the brain, inflammatory infiltrates in the liver, and acinar cell vacuolization with islet distortion in the pancreas. In contrast, MBIH and FBIH restored glycemic control, lipid profiles, inflammatory and hepatic renal markers, replenished GSH, and upregulated antioxidant genes via robust Nrf2 activation. Conclusions: These findings demonstrate that IAA-based hydrazone derivatives MBIH and FBIH afford superior protection against Cd-induced multi organ injury compared to ascorbic acid. Full article

Continuing our work in the field of synthesis and research of amino acids, their derivatives, and cyclization products, in this work, we synthesized various 3-(6-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)propanoic acid derivatives and investigated their antimicrobial activity. A total of eighteen synthesized chemical compounds (No. 1–18), including several structural analogues (e.g., 3a, 3b, 4a–4e, 8a–8m, 9a–9d), were evaluated for their antibacterial properties. The antibacterial activity was assessed using the Kirby–Bauer disk diffusion method, and inhibition zone diameters (mm) were measured against five representative bacterial strains: S. aureus, MRSA, B. subtilis, E. coli, and P. aeruginosa. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of the most active synthesized compounds were determined against representative Gram-positive and Gram-negative bacterial strains, including S. aureus, MRSA, B. subtilis, and E. coli. Overall, these results indicate that the tested compounds display selective antibacterial activity, mainly against Gram-positive bacteria, with compound 12 emerging as the most promising derivative in the series. The antibacterial activities of several synthesized compounds were systematically evaluated against S. aureus and MRSA over a 24 h incubation period, with optical density measured at ten time points. Bacterial growth was monitored spectrophotometrically at 600 nm (OD₆₀₀) at 1, 2, 3, 4, 5, 6, 7, 8, 20, and 24 h, enabling a detailed assessment of growth kinetics and the temporal dynamics of inhibition. The effect of compound 11 on the growth kinetics of S. aureus was evaluated by quantifying viable bacterial counts (log₁₀ CFU/mL) over a 6 h incubation period, and the results are presented in the time–kill curve. Compound 11 was selected for this experiment because it exhibited the most pronounced antibacterial activity against S. aureus in the disk diffusion assay. The cytotoxicity of compounds 9a, 11, 12, and 13 was evaluated at concentrations ranging from 125 to 1.95 µg/mL. The results showed a clear, concentration-dependent decrease in cytotoxicity for all tested compounds. The molecular structure of compound 3a was confirmed by a single-crystal X-ray diffraction. Full article

Saturated fatty aldehydes are products from lipid oxidation that negatively affect the organoleptic properties and nutritional quality of food and represent a risk to human health. For this reason, they are frequently used as indicators of oxidation in food safety. Usually, their determination is carried out by derivatization using an excess of 2,4-dinitrophenylhydrazine (DNPH), but the excessive use of derivatizing agents requires a high proportion compared to the analyte concentration to ensure a complete reaction, which causes interferences and limits the chromatographic separation of derivatized products. In this context, the encapsulation of DNPH in alginate spheres is proposed to determine aldehydes concentration in edible vegetable oil samples, allowing the gradual release of DNPH to form the corresponding hydrazones, which were subsequently separated and analyzed by HPLC-DAD. The proposed method was optimized by a Taguchi L₉(3⁴) experimental design, validated, and applied for the determination of aldehydes in edible oils. Limits of detection in the intervals of 0.77 to 1.41 mg L⁻¹ were obtained with adequate precision (expressed as relative standard deviation < 10%), which are suitable values for monitoring lipid oxidation in foods The proposed methodology represents a viable alternative to apply in quality control studies and lipid degradation profiles. Full article

The metallogelation process has been successfully achieved by utilizing a crystal engineering approach to generate a new metallogel. While the coordination of metal ions to ligands plays a very important role for building the primary structure, the stabilization and morphology of metallogels are heavily dependent on various intra-molecular interactions and non-covalent interactions, with hydrogen bonding (HB) often playing a dominant and structurally organizing role. In the present study, gelation experiments were achieved successfully by reacting vanadium acetylacetonate with a hydrazone ligand using different solvents. The metallogel shows excellent gelation ability with 1.7 wt% minimum gelator concentrations and the gel–sol dissociation temperature, T_gel is 55 °C (water/methanol). The structural properties of the metallogel were studied using single-crystal X-ray crystallography. The crystal structure analysis of the metallogel shows the presence of various interactions such as hydrogen bonding, pi–pi interactions, pnictogen bonding, and other weak non-covalent interactions. These molecular interactions play a very important role in the gelation process and also affect the gel’s properties like swelling behavior, viscosity, and elasticity. Full article

Pseudomonas aeruginosa biofilm-associated infections present higher recalcitrance to antimicrobial treatments, contributing to persistent and difficult-to-treat infections. Quorum sensing (QS) regulates various cellular processes that are important for the establishment and survival of microbial communities on the host. However, QS inhibitors for the treatment of P. aeruginosa biofilms remain under-researched, partly due to the complexity of QS signalling pathways and the challenge of developing non-toxic inhibitors. Herein, the bioactivity of 2-{(2E)-2-[1-(pyridin-2-yl)ethylidene]hydrazinyl}-1,3-thiazole-4-carboxylic acid (TTNF37), a novel pyridine-based thiazolyl-hydrazone (PTH), was investigated. The compound antimicrobial activity was evaluated against a broad spectrum of microorganisms, its antioxidant potential was assessed using different assays, and its QS-inhibitory effect on P. aeruginosa was studied using bioreporter strains. The effect on P. aeruginosa biofilm formation was analysed in terms of biomass, culturability, and metabolic activity, structure, and cell membrane integrity, while virulence factors were evaluated through absorbance measurements. In addition, molecular docking studies were performed to predict the drug’s interactions with essential QS proteins and biological targets. TTNF37 exhibited potent antimicrobial activity with low to moderate minimum inhibitory concentrations against clinically relevant Gram-negative and Gram-positive bacteria, as well as fungi and yeasts. It also showed antioxidant activity, with variable effectiveness across different radicals and systems. TTNF37 inhibited the 3-oxo-C12-HSL-dependent QS system of P. aeruginosa in a dose-dependent manner, with reductions ranging from 26% to 98%. It also impaired the production and detection of 3-oxo-C12-HSL, resulting in a 56% and 65% decrease in bioluminescence, respectively. Molecular docking studies revealed strong binding interactions with LasI and LasR proteins, with affinity values exceeding those of furvina, a known potent QS inhibitor. Molecular dynamics simulations validated stable TTNF37 binding to LasR and LasI. Both experimental and docking data indicate a significant interaction with human serum albumin (HSA). TTNF37 also significantly reduced pyocyanin production and prevented biofilm set-up with a reduction of 50% in biomass with pronounced alterations in biofilm structure. These results indicate the potential of TTNF37 and related PTHs for treating biofilm-associated infections. Full article

Five zinc(II) complexes based on N-[[2-(p-tolylsulfonylamino)-phenyl]-methyleneamino]-4R-benzamides were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, ¹H NMR and single-crystal X-ray analysis. Crystallographic studies reveal that the complexes have a polymer structure in the solid state. Acylhydrazones and zinc(II) complexes demonstrate effective photoluminescence in solutions and in the solid state. Preliminary studies have shown that the studied complexes can be used as emitters in OLED devices and for the bioimaging of pathogenic processes at the cellular level. 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