Search Results (96)

Protein kinases have key roles in cells as they regulate diverse signal transduction pathways. Mitogen-activated protein kinase (MAPK) signaling route modulates several processes, such as cell proliferation, cell programming, metabolic changes and stress responses. Within the group of proteins participating in this pathway, the MAPK kinase (MEK1) is a dimeric, 393-residue-long, dual-specificity protein kinase that phosphorylates both tyrosine and threonine residues. In this study, we explored the conformational changes occurring during the unfolding of MEK1, by using orthogonal biophysical techniques. Intrinsic fluorescence, extrinsic 8-anilinonapthalene-1-sulfonic acid (ANS) fluorescence, dynamic light scattering (DLS), and far-ultraviolet (UV) circular dichroism (CD) showed that the protein acquired a native-like conformation within a narrow pH range (8.0 to 9.0). Urea and guanidinium hydrochloride (GdmCl) denaturations followed by intrinsic and ANS fluorescence and far-UV CD, at pH 8.1, where the protein acquired a native-like conformation, showed that: (i) the apparent conformational stability of isolated MEK1 was low; and (ii) the unfolding occurred through the presence of intermediates. The presence of several unfolding intermediates was also evidenced through: (i) differential scanning calorimetry (DSC) in the absence of the ligand ATP; and (ii) unfolding simulations with the help of computational techniques based on constraint network analysis (CNA). We propose that the apparent low stability of this protein was related to its flexibility and modulates its ability to interact with diverse molecular partners. Full article

In the present study, a series of isoxazole derivatives were severally evaluated for their antifungal activity against the yeast Candida albicans and molds such as Aspergillus niger, Aspergillus flavus, and Fusarium oxysporum. The results demonstrate that the isoxazole derivatives exhibit considerable antifungal potential, particularly isoxazole-sulfonate ester 4b (Ar= 4-(Cl)C₆H₄, Ar′= 4-(CH₃)C₆H₄), which was found to be active with significant inhibition zones; the diameters of the C. albicans and F. oxysporum samples were measured at 17.00 ± 0.00 mm and 14.00 ± 0.00 mm, respectively. Furthermore, compounds 4a (Ar= 4-(CH₃)C₆H₄, Ar′= 4-(CH₃)C₆H₄), 4c (Ar: 4-(Cl)C₆H₄, Ar′: 4-(NO₂)C₆H₄) and 4d (Ar: 4-(Cl)C₆H₄, Ar′: 3-(Cl)-2-(OCH₃)C₆H₃) demonstrated MIC and MFC values of 20 µg/mL against C. albicans. In addition, the anti-hemolytic activity of these derivatives was evaluated. Compounds 4a, 4e (Ar: 4-(Cl)C₆H₄, Ar′: 3,4-(OCH₃)₂C₆H₃) and aroylisoxazole 3a (Ar: 4-(CH₃)C₆H₄) demonstrated a high degree of anti-hemolytic activity (>99%) at all concentrations evaluated (10, 15, and 20 mg/mL). Molecular docking and molecular dynamics studies over 200 ns revealed protein–ligand complexes to have high affinity and stability, which agrees with the experimental results. The compounds 4d, 4e, and 3a have shown significant interaction with the target proteins of C. albicans, A. flavus, and F. oxysporum, respectively. The results have revealed that the major interaction sites are hydrogen bonding, hydrophobic interactions, and the presence of a water molecule, especially with key residues like TYR_84, ASP_120, SER_90, and THR_89. The crystal structure of compound 4a was also obtained. Full article

In the present work, a novel series of eleven sulfonate derivatives with potent inhibitory activity against butyrylcholinesterase (BChE) is reported. Of these, compounds 2-[(E)-(2-Benzoylhydrazinylidene)methyl]phenyl 5-(dimethylamino)naphthalene-1-sulfonate (5c, IC₅₀ = 1.11 µM) and tert-butyl (2E)-2-[(2-{[5-(dimethylamino)naphthalene-1-sulfonyl]oxy}phenyl)methylidene]hydrazine-1-carboxylate (5b, IC₅₀ = 11.51 µM) exhibit stronger inhibitory activity than rivastigmine, the reference compound, and exhibit high selectivity for BChE over AChE (e.g., selectivity index 57 for 5c). Interestingly, compound 5c also exhibited anti-inflammatory effects, which is important for potential therapeutic applications, especially in Alzheimer’s disease. These new compounds were designed through a structure-based approach using molecular modeling techniques (docking, molecular dynamic (MD) simulations, and QTAIM (quantum theory of atoms in molecules) calculations). The most promising compounds show no detectable toxic effects and satisfy Lipinski’s rule of five, indicating that they represent attractive starting structures for the design of new derivatives acting as specific BChE inhibitors. In addition, our results indicate that relatively simple computational techniques such as docking calculations and toxicity prediction programs can be valuable when properly used in the search of new candidates for this particular target. Docking calculations show that the more active compounds of this series reach the bottom region of the gorge interacting with residues within the active site of BChE. However, our data further suggest that the use of more precise techniques, such as MD simulations and QTAIM analysis, is necessary to obtain detailed insight into ligand–enzyme interactions. Regarding QTAIM calculations, they demonstrate that such computations are very useful to evaluate the molecular interactions of the different molecular complexes. In summary, we report a new series of sulfonate derivatives as promising starting structures for the development of new selective BChE inhibitors. Full article

The purpose of this work was to study water-soluble platinum complexes as potential therapeutic agents. We used water-soluble platinum(II) complexes containing sulfonated N-heterocyclic carbene ligands (NHC), applied on two human cell models: human NB4 acute promyelocytic leukemia and PC3 prostatic cancer cells. We studied the toxic effects on these two types of human tumor cells. We analyzed metabolic activity, membrane damage, cell cycle, DNA fragmentation and programmed cell death. In human NB4 leukemia cells, the water-soluble dimethyl NHC complex 5Me proved highly toxic. It extinguished cell metabolism at 1 mM for 24 h. This treatment gave rise to the presence of fragmented DNA (subdiploid DNA). This compound promoted programed cell death in 60% of the cells. At longer times, the treatments produced neither higher fragmentation of DNA nor augmented apoptosis. 5Me complex, at 100 µM, showed slight toxicity on NB4 cells. In PC3 cells, dimethyl complex 5Me (1 mM for 24 h) is less toxic (reduced DNA fragmentation and programmed cell death) than in NB4 cells. Mono-NHC complexes 4 and 5 treatments at a high concentration for 24 h on PC3 cells produced apoptosis (30% of the cells) but their damage on cell permeability and DNA fragmentation was weak. Thus, PC3 cells are more resistant to NHC platinum(II) complexes than NB4 cells. Full article

Gold nanoparticles (AuNPs) are of significant interest due to their unique properties and applications in biomedicine. While hyaluronic acid (HA) has been used to modify pre-formed AuNPs, its thiolated derivative (HA−SH) has been less explored for the direct synthesis and stabilization of AuNPs. This study investigates the use of thiolated hyaluronic acid as a key component in the synthesis of AuNPs. A series of HA-AuNPs (HA-AuNP1-4) were synthesized by reacting HA-SH with HAuCl₄ at different mass ratios. The resulting nanoparticles were characterized using UV-Vis spectroscopy, scanning/transmission electron microscopy (SEM/STEM), X-ray photoelectron spectroscopy (XPS), photon cross-correlation spectroscopy (PCCS), and zeta potential measurements. The chemical transformations of the thiol ligand were studied using NMR spectroscopy. The morphologies and sizes of AuNPs depended on the HA-SH-to-HAuCl₄ ratio, ranging from icosahedral and triangular particles (≥146 nm) to quasi-spherical particles with a bimodal distribution (6–7 nm and 45–60 nm). XPS confirmed the presence of metallic gold (Au⁰) and a Au−S bond, while NMR and XPS revealed the partial oxidation of thiol groups to sulfonic acid. Zeta potential measurements showed that lower HAuCl₄ concentrations resulted in higher negative charge (up to −41.5 mV), enhancing colloidal stability. This work demonstrates a versatile approach to the synthesis of hyaluronic acid-based gold nanomaterials with tunable properties for potential biomedical applications. Full article

The effects of saponin-rich extracts on pancreatic lipase activity were examined. Horse chestnut seed and ginseng root extracts stimulated lipase activity the most, while ivy leaf and fenugreek seed extracts had an inhibitory effect. The strongest antiradical activity (ABTS^+•–2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) test) was exhibited by horse chestnut seed extract and the weakest by the soapwort root extract. Antioxidant activity strongly positively correlated with the total amount of phenols. Experimental studies showed that the surface properties of saponins present in extracts influence emulsion stabilization and have a moderate stimulating or inhibitory effect on pancreatic lipase activity. Computational studies demonstrated that lipase activity is stimulated by stabilizing an oil emulsion in the case of all studied saponins. Depending on the type of saponin, activation or inhibition of lipase was observed due to the immediate ligand–enzyme interactions. Full article

The reaction of 4′–bromo-fenamic acid, a bromo-derivative of fenamic acid (the scaffold of the fenamate non-steroidal anti-inflammatory drugs), with Co(II) in the absence or presence of various nitrogen-donor ligands yielded nine novel, neutral mononuclear Co(II) complexes. These complexes were characterized by physicochemical and spectroscopic techniques and single-crystal X-ray crystallography. The biological evaluation of the compounds focused on their antioxidant and antimicrobial efficacy, as well as their interaction with calf-thymus DNA, pBR322 plasmid DNA (in the absence or presence of diverse irradiations) and serum albumins. The complexes have shown significant antioxidant activity since they can scavenge 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals (up to 96.48 ± 0.07%) and reduce H₂O₂ (up to 96.93 ± 0.53%). Antimicrobial testing revealed that the complexes were more active than free 4′-bromo-fenamic acid with four of them classified as bactericidal agents against selected bacterial strains. The compounds can interact with calf-thymus DNA via intercalation, and the calculated DNA-binding constants are on the 10⁶ M⁻¹ order. The plasmid DNA-cleavage ability of the compounds is strongly enhanced under UVA irradiation (photocleavage > 90%). In addition, the compounds can bind tightly and reversibly to serum albumins with binding constants in the 10⁵ M⁻¹ range. Full article

Diaza-peptidomimetics are constrained compounds that mimic the biological efficacy of peptides while offering increased stability. We have previously reported the synthesis of bis-cyclic guanidine heterocyclic peptidomimetics as opioid ligands with mixed μ-, κ- and δ-opioid receptor interactions and their potential activity as novel analgesics. Using the same approach, we report here the synthesis of sulfonated and piperazine-tethered bis-cyclic guanidines and their in vitro screening results from radioligand competition binding assays at the μ- (MOR), δ- (DOR), and κ- (KOR) opioid receptors. Full article

The deep defluorination of water remains a significant environmental challenge. In this work, aluminum was loaded onto the bifunctional resin S957 containing a phosphoric-sulfonic acid difunctional group for efficient fluoride removal. Al-S957 demonstrated excellent fluoride removal performance across a broad pH range. When anions and organics coexisted, Al-S957 exhibited significantly better fluoride adsorption performance compared to aluminum-loaded monofunctional resins. The adsorption followed an endothermic chemisorption process on a monolayer surface. FTIR and XPS analyses further revealed that fluoride removal relied on a ligand exchange mechanism. Column adsorption conducted over five cycles highlighted the strong practical potential of Al-S957. The results suggested that Al-S957 exhibits significant potential for practical applications. Full article

A nitro-derivative of fenamic acid (4′–nitro–fenamic acid) was synthesized and used as ligand for the synthesis of four Co(II) complexes in the absence or presence of the N,N′-donors 2,2′–bipyridylamine, 1,10–phenanthroline and 2,9–dimethyl–1,10–phenanthroline. The characterization of the resultant complexes was performed with diverse techniques (elemental analysis, molar conductivity measurements, IR and UV-vis spectroscopy, single-crystal X-ray crystallography). The biological evaluation of the compounds encompassed (i) antioxidant activity via hydrogen peroxide (H₂O₂) reduction and free radical scavenging; (ii) antimicrobial screening against two Gram-positive and two Gram-negative bacterial strains; (iii) interactions with calf-thymus (CT) DNA; (iv) cleavage of supercoiled pBR322 plasmid DNA (pDNA), in the dark or under UVA/UVB/visible light irradiation; and (v) binding affinity towards bovine and human serum albumins. The antioxidant activity of the compounds against 2,2′–azinobis–(3–ethylbenzothiazoline–6–sulfonic acid) radicals and H₂O₂ is significant, especially in the case of H₂O₂. The complexes exhibit adequate antimicrobial activity against the strains tested. The complexes interact with CT DNA through intercalation with binding constants reaching a magnitude of 10⁶ M⁻¹. The compounds have a significantly enhanced pDNA-cleavage ability under irradiation, showing promising potential as photodynamic therapeutic agents. All compounds can bind tightly and reversibly to both albumins tested. Full article

Metal complexes of endogenous metals, such as iron, copper, and zinc, offer a biocompatible, cost-effective, and eco-friendly alternative to heavy metals for drug design. This study presents the synthesis, structural characterization, and evaluation of the biological activity of eight novel iron(III) complexes with substituted salicylaldehydes as ligands. The characterization of the complexes involved spectroscopic and physicochemical methods. The structures of two complexes were determined using single-crystal X-ray crystallography. The biological studies of the complexes focused on the interaction of calf-thymus DNA, the (photo)cleavage of pBR322 plasmid DNA (pDNA), the affinity for bovine and human serum albumins, and the antioxidant activity. The complexes interacted with calf-thymus DNA via intercalation with high DNA-binding constants. The complexes exhibited high pDNA-cleavage ability, which is significantly enhanced upon exposure to UVA or UVB irradiation. The complexes can bind tightly and reversibly to both serum albumins, and their binding locations were identified. Finally, the complexes showed moderate ability to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals with a high ability to reduce hydrogen peroxide. Full article

Antibiotic resistance is a problem repeatedly reported by health authorities. Metalloantibiotics, i.e., biologically active compounds containing one or more metal ions, can be an important resource in the fight against bacteria and fungi. Here, we report the results obtained with a panel of copper(II), nickel(II) and zinc(II) complexes with thiosemicarbazone, semicarbazone and acylhydrazone ligands on Staphylococcus aureus, Escherichia coli and Candida albicans, taken as model systems of human pathogens. To increase the solubility in water, the sulfonic group was introduced on some of the ligands, isolating them as sodium salts (NaH₂L4-NaH₂L7). Complexes 1–14 were isolated, fully characterized and the X-ray structures of 11, 12 and 13 were obtained. While all the ligands have no antimicrobial activity, the copper(II) complexes 1 and 4 and the nickel(II) complex 2, obtained from thiosemicarbazone ligands, showed good activity, in particular against S. aureus; these complexes were investigated in depth, calculating their respective IC₅₀ values (4.2 μM, 3.5 μM and 61.8 μM, respectively). It should be noted that nickel(II) complex 2 does not show hemolytic activity and has a favorable SI value. While all the copper(II) complexes completely degraded the plasmid DNA in presence of H₂O₂, nickel(II) complex 2 cleaved the plasmid DNA leading to the formation of the relaxed nicked conformation, thus suggesting a different mechanism of action. Full article

In this study, the structure of the synthesized Zn(II) complex with homovanillic acid (HVA) was investigated using the FT-IR, UV/Vis, and NMR spectroscopic methods, as well as elemental and thermal (TG, DTG, and DSC) analysis. The stoichiometric molar ratio of metal:ligand for the solid form of the complex was established as 1:2, with coordination through the carboxylate group and aromatic ring substituents. The theoretical structural and electronic parameters were calculated by the use of the B3LYP/6-311++G(d,p) method. Antioxidant properties were examined using spectroscopic tests: DPPH (1,1-diphenyl-2-picrylhydrazyl radical), FRAP (ferric reducing antioxidant activity), and ABTS (2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (diammonium salt radical cation). The Zn(II) complex with HVA showed similar or lower antioxidant properties compared to the ligand, depending on the antioxidant assay. The antimicrobial activity of acid and its complex with Zn(II) against Escherichia coli, Bacillus subtilis, and Candida albicans were also investigated by evaluation of the minimum inhibitory concentration (MIC). The Zn(II) complex shows higher antibacterial and antifungal activity compared to HVA. Full article

The precise construction and programmable assembly of structures with specific topologies remain persistent challenges in crystal engineering, primarily constrained by the limited availability of building blocks. Utilizing a synergistic approach that combines an in situ-formed concave polyoxovanadate (POV) cluster {VV₄} with specifically designed 120° ditopic carboxylic acid bridging ligands, we successfully synthesized a series of wine-rack-type supramolecular macrocycles characterized by the general formula [(V₅O₉Cl)₄(L)₈]⁸⁻. The experimental results demonstrate that the introduction of sulfonic acid groups enables controlled structural extension into 1D chain and 2D layer architectures, manifesting the unique advantages of POV-based wine-rack units in constructing framework-based porous materials. This work significantly contributes to the structural diversity of wine-rack-type supramolecular architectures while simultaneously highlighting the great potential of polyoxometalate-driven supramolecular assemblies in materials science. Full article

Heterocyclic aromatic amines (HAAs), known for their mutagenic and carcinogenic potential, are formed during the heating of protein-rich food items. Detecting HAAs swiftly and accurately poses challenges due to complex food matrices and low HAA concentrations. In this study, a simple and efficient magnetic solid-phase extraction (MSPE) strategy was developed for the simultaneous isolation and enrichment of three HAAs such as 2-amino-3,4,8-trimethylimidazo [4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx), and 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) in processed meats, employing the magnetic covalent organic framework Fe₃O₄@MOF-545-AMSA as an adsorbent. It was synthesized via a solvothermal method, with Fe₃O₄ as the magnetic core. Its building blocks are as follows: zirconium (Zr) as the coordination metal ion, tetrakis(4-carboxyphenyl)porphyrin and benzoic acid as organic ligands, and aminomethanesulfonic acid (AMSA). This composite captures targeted HAAs efficiently by exploiting the unique porous MOF-545-AMSA structure, specific metal–ligand coordination, and AMSA’s amino and sulfonic acid groups. The quantification of HAAs was achieved through the combination of Ultra-Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) and MSPE, demonstrating satisfactory linearity (R² ≥ 0.9917), high recovery rates (83.7–111.0%), and low detection limits (0.1–1.0 μg/kg). Moreover, an automated high-throughput detection system was developed using MSPE to assess the presence of HAAs in meat products. Full article