Search Results (993)

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. Curcumin (CUR) is a polyphenol with several biological properties, including antimicrobial effects. However, its low bioavailability remains a challenge, and nanoencapsulation may represent a useful strategy to overcome this limitation. This study aimed to evaluate, in vitro, the antipromastigote activity of free CUR and the antiamastigote effect of CUR nanoparticles and their association with antimoniate, as well as to elucidate possible mechanisms of action. Free CUR directly inhibited promastigote proliferation, with an IC₅₀ of 25 µM at 24 h. CUR induced mitochondrial hyperpolarization, increased the production of reactive oxygen species (ROS) and nitric oxide (NO), and enhanced lipid peroxidation and the accumulation of lipid droplets in promastigotes. These alterations were associated with autophagic and apoptotic processes, morphological and ultrastructural changes, DNA fragmentation, and cell cycle arrest. Free CUR also reduced the viability of BALB/c peritoneal macrophages, and this effect was attenuated after nanoencapsulation. Free CUR, CUR nanoparticles, and their association with antimoniate (AM) reduced both the percentage of infected macrophages and the number of intracellular amastigotes at all tested concentrations, with increased NO production observed at the highest concentrations of free CUR. Altogether, our findings suggest that CUR exerts leishmanicidal activity against promastigotes by disrupting oxidative metabolism and triggering autophagic and apoptotic pathways, while amastigote elimination appears to occur through mechanisms independent of oxidative stress. Full article

Ninhydrins represent a promising chemical space for the search for new biologically active molecules with antimicrobial, antiprotease, and antitumor properties. In the present work, new ninhydrin derivatives were synthesized, and for the first time, a systematic in silico study of ninhydrins as multitarget ligands for five pharmacologically significant targets (HER1/HER4, HER2/HER3, Trk-B, PPAR-α, and LTβR) was conducted, whose amplification or overexpression plays a key role in the pathogenesis and progression of certain aggressive cancer types. Among the studied ninhydrin derivatives, compound 1 (2,2-dihydroxy-5,6-dimethoxy-1H-indene-1,3(2H)-dione) stands out as the most potentially active molecule. It exhibits high affinity for HER1/HER4, Trk-B, and PPAR-α, opening up potential applications in oncology (HER family and Trk-B inhibition during BDNF overexpression), neurodegenerative diseases (Trk-B modulation), and metabolic disorders (PPAR-α activation). Compound 4 (2,2-Dihydroxy-5-trifluoromethylindane-1,3-dione) is a leader in LTβR binding and also holds promise for immuno-oncology and anti-inflammatory strategies. Full article

Melanoma is a highly aggressive and metabolically adaptable cancer that often resists conventional therapies. Targeting core bioenergetic pathways may, therefore, represent an effective strategy to improve therapeutic responses, particularly in tumors dependent on mitochondrial function. SC18 is an imidazolidine-2,4-dione compound that binds the NADH-binding pocket of voltage-dependent anion channels (VDACs), inducing mitochondrial dysfunction. VDAC expression is increased in melanoma and strongly associated with advanced disease stage and poor prognosis. In this study, we evaluated the effects of SC18 in melanoma cell lines with distinct pigmentation states, including melanin-rich melanotic human MNT-1 and mouse B16-F1, as well as low/amelanotic human SKMel28 and mouse YUMM cells. VDAC1, VDAC2 and VDAC3 were highly expressed across these melanoma lines, all of which relied on both glycolysis and mitochondrial oxidative phosphorylation for ATP production. SC18 reduced mitochondrial membrane potential and oxygen consumption rates, accompanied by declines in intracellular ATP levels and TCA cycle substrate utilization. SC18 also increased reactive oxygen species, mitochondrial superoxide, and lipid peroxidation, indicating enhanced oxidative stress. These metabolic and redox disturbances were associated with reduced cell viability and significantly impaired migration in multiple melanoma cell lines, supporting a potential anti-metastatic effect. In addition, SC18 showed synergistic cytotoxicity when combined with other chemotherapeutic agents. Overall, SC18 disrupted mitochondrial metabolism, induced oxidative stress, and impaired survival and motility pathways, with more pronounced effects in low/amelanotic than in melanotic melanoma cells. Together, these findings support the further development of SC18 as a mitochondrial metabolic disruptor that targets redox vulnerabilities in melanoma. Full article

We report the synthesis, characterisation and electronic modulation of three novel fused polyheterocyclic ligands—naphtho[1,2-b]furan-4,5-dione (1), furo[3′,2′:3,4]naphtho[1,2-d]imidazole (2), and benzo[a]furo[2,3-c]phenazine (3)—and their Cu(II), Zn(II) and Fe(II/III) complexes. Compound (1) was isolated at 96.5% yield using fulvic acid as a green organocatalyst. ⁵⁷Fe Mössbauer spectroscopy identified two high-spin Fe(III) environments in a 37:63 ratio (δ = 0.377 mm s⁻¹; Δ = 0.62 and 1.01 mm s⁻¹), with no evidence of magnetically ordered oxide phases. Six enantiomeric metal malate salts were synthesised at 86–93% yield for spectrophotometric titrations. The key finding is a striking Cu(II)-specific enantioselective molecular recognition: (3) binds (S)-(−)-malate Cu(II) with log K = 9.02, a factor of 2.5× higher than the (R)-(+)-malate complex (log K = 8.62), while Fe(II) and Zn(II) show no enantioselectivity. These results establish chiral counter-ion engineering combined with π-conjugated polyheterocyclic scaffolds as a powerful strategy for chiroptical sensing and asymmetric catalysis. Full article

The yellow mealworm (Tenebrio molitor, Linnaeus) is a cosmopolitan pest of stored grains, causing losses up to 15%. Due to the environmental and health risks of synthetic fumigants, botanical alternatives are needed, but their ecotoxicological assessment is also required. Thus, the aim of this study was to assess the insecticidal, insectistatic, and ecotoxicological effects of Salvia connivens (Epling) dichloromethane extract and to identify its compounds. Insecticidal and insectistatic activities were assessed through the consumption of an artificial diet containing the extract over 30 days. Ecotoxicological activity was evaluated through acute toxicity assays on Danio rerio (Hamilton) adults and embryos. The extract showed insecticidal activity against T. molitor achieving 50% mortality at 10,000 ppm (LC₅₀ = 9367.19 ppm). Additionally, at 10,000 ppm larval weight gain was reduced by 53.37% at 30 days compared to the control. Ecotoxicological assays revealed slight toxicity toward D. rerio adults (LC₅₀ = 84.27 ppm) and embryos (LC₅₀ = 32.60 ppm). GC-MS analysis identified hexadecanoic acid (7.08%), 1-(2-methoxyphenyl)-2,5-dihydro-1H-pyrrole-2,5-dione (6.30%), cis-9-octadecenoic acid (3.91%), β-sitosterol (3.05%), and eicosane (3.00%) as the major constituents according to the chromatographic method used. These findings suggest that S. connivens dichloromethane extract is a potential botanical product for T. molitor management. Full article

We report the synthesis of the new compound 2-chloro-4,5,6,7-tetrafluoro-2-(methylthio)-1H-indene-1,3(2H)-dione (Compound 3), which presents an important type of fluoro-containing heterocycles and is a useful intermediate product in organic synthesis. The structure of the compound was confirmed by the NMR and elemental analysis. A quantum-chemical comparison (DFT) of 2-chloro-2-(methylthio)-1H-indene-1,3(2H)-dione (with C-H bonds, compound 4) and its 4,5,6,7-tetrafluoro derivative (with C-F bonds, compound 3) at the M06-2X/6-311++G(d,p) level in THF showed that the introduction of four fluorine atoms into the benzene ring causes a systematic shortening of the C=O, C-Cl, and C-C bonds of the five-membered ring, as well as an almost twofold decrease in the dipole moment. Replacing hydrogen with fluorine leads to a simultaneous stabilization of the frontier orbitals and a narrowing of the HOMO–LUMO energy gap, while the electron affinity increases by 0.39 eV and the electrophilicity index increases from 2.77 to 3.24 eV, making compound 3 a strong electrophile. Analysis of donor–acceptor interactions (NBOs) and condensed Fukui indices confirms that perfluorination selectively increases the electrophilicity of the sp³-carbon center of C-Cl, making it more susceptible to nucleophilic attack. At the same time, the isodesmic reaction with 1,2,4,5-tetrafluorobenzene yields a positive free energy change (ΔG = +13.4 kcal/mol), indicating that the increased reactivity of compound 3 is kinetic rather than thermodynamic in nature. The synthesized 1,3-indandione derivative thus represents a promising precursor for tetrafluoroninhydrin and can be considered a biologically active compound. Thus, perfluorination of the indandione skeleton is an effective tool for targeted enhancement of electrophilic properties without fundamentally changing the geometry of the molecule, which opens up prospects for the design of new highly reactive reagents. Full article

A series of 1,2,3-triazole-linked-thiazolidine-2,4-dione hybrids (SDP1–SDP15) were designed, synthesized, and evaluated for their antidiabetic potential. All structures were characterized by FT-IR and NMR spectroscopy (¹H and ¹³C). All derivatives exhibited significant in vitro inhibition of α-glucosidase (IC₅₀: 24.17–46.41 µg/mL) and α-amylase (23.25–50.66 µg/mL), comparable to the standard drug acarbose (IC₅₀: 25.18 and 32.53 µg/mL) and superior to the reference drug pioglitazone (IC₅₀: 84.24 and 79.74 µg/mL) for α-glucosidase and α-amylase, respectively. Molecule SDP8 emerged as the most potent with an IC50 of 24.17 and 23.25 µg/mL for α-glucosidase and α-amylase, respectively. Further, SDP8 exhibited a higher docking score of −10.7 kcal/mol and −10.4 kcal/mol against α-glucosidase and α-amylase than pioglitazone (−8.1 kcal/mol and −7.7 kcal/mol, respectively), suggesting that interaction with these two enzymes may be the cause for its antidiabetic activity. Furthermore, DFT analysis revealed favorable electronic properties with a low HOMO-LUMO energy gap, whereas ADMET predictions revealed moderate drug-like characteristics with some limitations, such as poor solubility, relatively high lipophilicity, and partial noncompliance with drug-likeness regulations. Overall, these results highlight triazole-linked thiazolidinedione hybrids as promising candidates for further development in T2DM, with SDP8 serving as a preliminary lead requiring additional optimization and validation. Full article

Chemical recycling of mixed plastic waste can recover hydrocarbon products, but additive-derived non-intentionally added substances (NIASs) and other volatile or extractable residues may affect product quality and safety. In this study, six polyolefin-rich waste streams (P1–P6) were analyzed by analytical pyrolysis coupled with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (Py–GC×GC–TOF–MS), while three additional consumer-grade plastics (P7–P9) were examined by headspace/solvent-extraction GC–MS and aqueous migration testing to profile volatile organic compounds (VOCs), semi-volatile organic compounds (SVOCs), and water migrants. Under rapid pyrolysis at 650 °C, the condensable products were dominated by C5–C30 aliphatic hydrocarbons. Polyethylene (PE)-rich feeds produced mainly n-paraffins and α-olefins, whereas polypropylene (PP)-rich feeds produced more branched olefins and modest mono-aromatics. Oxygenated compounds were negligible in non-oxidized feeds, but persisted at low levels in weathered high-density polyethylene (HDPE), consistent with pre-existing oxidation. Antioxidant-derived NIASs, including 2,4-di-tert-butylphenol and an Irganox 1010-related spiro-dione, were detected at trace to low area-fraction levels. VOC/SVOC and migration analyses revealed mainly low-intensity hydrocarbons, esters, antioxidant-related degradation products, caprolactam, and selected plasticizer-related compounds. These results show that relatively clean polyolefin streams can yield hydrocarbon-rich pyrolysates, but oxidized PE and additive-derived NIASs remain important quality-control targets. The GC-based methods used here characterize the volatile, condensable, and readily extractable fraction and do not represent the total contaminant load of the source waste. Full article

The title compound, 3-(diphenylamino)-4-ethoxycyclobut-3-ene-1,2-dione (6), was prepared by reaction of diphenylamine (2) with diethyl squarate (DES; 5) as part of our ongoing studies on monosquarate-amides. Following purification and recrystallisation, the product was isolated as a green crystalline solid. Its structure was established by spectroscopic methods, including FTIR, ¹H NMR, ¹³C NMR and HRMS, and was unambiguously confirmed by single-crystal X-ray diffraction. This work provides access to a previously unreported diphenylamino-substituted squaric acid derivative. Full article

A hybrid method combining biomimetic liquid chromatography with immobilized artificial membrane (IAM) and quantitative structure–activity relationships (QSARs) was used to derive helpful models for predicting selected properties related to distribution (binding to human serum albumin (log P_w/HSA)) and absorption (skin permeation (log K_w/sp), plant cuticle permeation (log P_w/pc), and human intestinal permeability (Caco-2)), and therefore influencing the effectiveness or unwanted effects of 199 synthetic compounds that are regarded as potential drugs or plant protection products. The molecules under investigation—derivatives of 5H-6,7-dihydroimidazo [2,1-c][1,2,4]triazole, 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one, 2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione, 1H-1,2,4-triazole, carbamic and phenoxyacetic acid—differ in their properties but all meet the requirements for xenobiotics to be considered as medicinal products. Reliable high-concept models were developed, indicating lipophilicity, molecular size, electronic properties, and the number of rotatable bonds as descriptors that determine the biological properties of these compounds. These models have been optimized and cross-validated, confirming their reliability and high predictivity. Full article

Reagentless glucose biosensors with redox mediator—polymerized 1,10-phenanthroline-5,6-dione (pPD)—were developed and electrochemically investigated. Three types of biosensors based on graphite rod (GR) electrodes modified by (i) 13 nm of gold nanoparticles (AuNPs), (ii) electrochemically synthesized dendritic gold nanostructures (DAuNSs), and (iii) platinum nanostructures (PtNSs) were prepared. All electrodes were modified by glucose oxidase (GOx), and the pPD was polymerized for 2 h. Thus, GR/AuNPs/GOx/pPD, GR/DAuNSs/GOx/pPD, and GR/PtNSs/GOx/pPD electrodes were developed and electrochemically characterized. The electrode without noble metal nanostructures (GR/GOx/pPD) was used as the control. The biosensor based on the GR/DAuNSs/GOx/pPD electrode exhibited the best performance, with the sensitivity of 2.58 μA/(mM cm²), the linear range up to 93.7 mM, the limit of detection 0.182 mM, the reproducibility and repeatability of 4.99 and 4.80%, and the storage stability (50% of initial current responses (t_1/2)) for up to 19 days. The achieved high resistance to interfering materials enabled precise glucose detection in real samples, including human serum and beverages. The technological solutions presented in this paper are anticipated to provide opportunities and benefits of developing novel enzymatic reagentless glucose biosensors based on noble metal nanostructures for use in clinical assays and general diagnostics, including blood glucose monitoring in people with diabetes. Full article

Background/Objectives: Chronic inflammatory skin diseases are frequently associated with pruritus, in which the neurokinin-1 receptor (NK₁R) and its ligand substance P (SP) play a central role. The development of compounds combining anti-inflammatory and antipruritic effects represents a promising therapeutic strategy. This study aims to identify fiscalin B derivatives as anti-inflammatory agents with high affinity to NK₁R using an integrated in silico and in vitro approach. Methods: A library of fiscalin B derivatives was screened through molecular docking against NK₁R to identify high-affinity ligands. Selected compounds were further evaluated using in silico ADMET and toxicity predictions. In vitro assays were conducted in HaCaT keratinocytes, RAW264.7 macrophages, and NIH/3T3 fibroblasts to assess cytotoxicity, nitric oxide production, inflammatory proteins expression, and cell migration. Results: Docking studies identified several derivatives with predicted binding affinities comparable to or exceeding those of aprepitant, a well-established NK₁R antagonist. Several compounds, particularly 2, 3, 4, 6, and 7, reduced lipopolysaccharide-induced nitric oxide production to 41–51% without relevant cytotoxicity. This effect was associated with reduced iNOS protein levels, suggesting modulation of inflammatory pathways rather than direct nitric oxide scavenging. Most compounds showed positive safety profiles, although in silico analysis indicated limited biodegradability and potential aquatic toxicity. Conclusions: The fiscalin B derivatives, 2, 3, and 4, demonstrate potential as anti-inflammatory agents, in vitro, and as NK₁R high affinity ligands, in silico. These findings support their potential as lead compounds for topical therapies for inflammatory skin disorders associated with pruritus, although further optimization and validation are required. Full article

Alkyn-1,2-diones have gained great attention as useful building blocks in organic synthesis. Regioselective synthetic routes towards 3,5-disubstituted isoxazoles, containing the methylfuroyl or diterpenylfuroyl moiety at the C-3 or C-5 position from alkyne-1,2-diones 1, 2, 3, are reported. The reaction with hydroxylamine hydrochloride 6 in ethanol afforded the 1,2-addition products: 5-aryl-3-(methylfuran-2-carbonyl)isoxazoles (yield 61–94%) or 16-(5-arylisoxazole-3-carbonyl)labdatrienes (yield 48–97%). The reaction of alkynediones 1–3 with 6 in THF in the presence of triethylamine led to 5-hydroxy-4,5-dihydroisoxazoles and subsequent dehydration afforded regioisomeric 3-aryl-5-(methylfuran-2-carbonyl)isoxazoles or 16-(3-arylisoxazole-5-carbonyl)labda-trienes (yield 65–98%). New heterocyclic compounds exhibited significant analgesic action in acetic acid writhing and hot-plate tests, and the activity was comparable to reference drugs diclofenac sodium and celecoxib. Isoxazoles, which possessed the most analgesic activity, reduced the concanavalin A-induced inflammation by 34–51%; the effect was comparable to the drug indomethacin. The results of in vitro biological assays (MTT test) revealed that isoxazoles were non-toxic against the normal epithelial VERO cells, and 16-(3-aryl-5-hydroxyisoxazoline-5-carbonyl)labdatrienes 20–24 exhibited selective cytotoxicity against the breast adenocarcinoma MCF 7 (GI₅₀ = 4.7–8.3 μM) and cervical cancer cells C33 A (GI₅₀ = 3.4–4.7 μM). Molecular docking analysis to determine the binding potential of new molecules to the active site of human COX-1 and COX-2 enzymes was conducted. Full article

Periodontal status has been associated with infection in lung diseases such as chronic obstructive lung disease (COPD). However, evidence regarding its association with bronchiectasis remains limited, despite the shared clinical and pathophysiological characteristics between the two conditions. Therefore, the aim of the present study was to investigate whether periodontal treatment affects not only the microbiota of saliva but also that of sputum and nasal secretions in individuals with bronchiectasis. This single-center, parallel-group randomized controlled clinical trial included forty-nine individuals with bronchiectasis, who were randomly allocated using a predefined randomization sequence with allocation concealment to a conventional group (n = 26) submitted to mechanical periodontal treatment plus oral hygiene and a control group (n = 23) submitted to oral hygiene alone. Due to the nature of the intervention, participants and operators were not blinded. At the end of the study, all participants received periodontal treatment. The primary outcome was the quantitative assessment of Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Porphyromonas gingivalis (P. gingivalis) in sputum. Secondary outcomes included the quantification of these microorganisms in saliva and nasal secretions, as well as clinical periodontal parameters and quality-of-life assessment. All variables were evaluated at baseline and three months after treatment. Results: Periodontal treatment improved gingival and plaque indices in the conventional group compared with the control group. However, no significant differences were observed in sputum samples for any of the microorganisms analyzed, suggesting no measurable effect on bacterial levels in the lower airways within the study period. At the end of the experimental period, levels of P. aeruginosa and P. gingivalis decreased in nasal secretions, and levels of P. aeruginosa decreased in saliva in the conventional group but not the control group. No significant differences were found in S. aureus levels between groups or overtime. Also, no significant differences in total OHIP-14 scores were observed between groups. In conclusion, periodontal treatment was associated with reductions in P. aeruginosa in nasal secretions and saliva, and P. gingivalis in nasal secretions, in individuals with bronchiectasis and periodontitis. Periodontal treatment improved gingival and plaque indices in the conventional group compared with the control group. However, no significant differences were observed in sputum samples for any of the microorganisms analyzed, suggesting no measurable effect on bacterial levels in the lower airways within the study period. At the end of the experimental period, levels of P. aeruginosa and P. gingivalis decreased in nasal secretions, and levels of P. aeruginosa decreased in saliva in the conventional group but not the control group. No significant differences were found in S. aureus levels between groups or overtime. Also, no significant differences in total OHIP-14 scores were observed between groups. Full article