Search Results (899)

Background/Objectives: Antimicrobial resistance and bacterial persistence underscore the need to develop new chemotypes with multifunctional antibacterial mechanisms. This study aimed to design, synthesize, and evaluate curcumin-inspired 3,5-diarylidene-4-piperidones as versatile small molecules exhibiting antibacterial, antibiofilm, anti-efflux, DNA gyrase-inhibitory, and antiproliferative properties. Methods: A targeted series of triazole-conjugated 3,5-diarylidene-4-piperidones was synthesized through copper-catalyzed azide-alkyne cycloaddition click chemistry and subsequently characterized using standard spectroscopic techniques. The compounds were assessed for antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli. Selected active compounds underwent further evaluation for DNA gyrase inhibition, antibiofilm activity against multidrug-resistant S. aureus ATCC 33591, ethidium bromide accumulation, and antiproliferative effects on HCT116 and MCF7 cancer cells, with RPE1 cells serving as a control to evaluate cytotoxicity in normal cells. Additionally, computational studies, including QSAR analysis and molecular docking, were conducted to bolster structure–activity relationships and provide mechanistic insights. Results: Several derivatives demonstrated selective antibacterial activity against Gram-positive bacteria, particularly S. aureus, while exhibiting limited or no efficacy against E. coli. Compounds 7n and 7l emerged as the most potent against S. aureus, with minimum inhibitory concentrations (MICs) of 7.8 and 8.2 μM, respectively. Notably, compound 7l inhibited S. aureus DNA gyrase supercoiling, displaying an IC₅₀ of 3.20 μM, comparable to ciprofloxacin. Compound 7e exhibited the strongest antibiofilm activity against multidrug-resistant S. aureus, whereas compound 7a resulted in the highest accumulation of ethidium bromide, indicating robust anti-efflux activity. Antiproliferative assays revealed that select halogenated derivatives were effective against HCT116 and MCF7 cells, while the most promising antibacterial compounds exhibited minimal cytotoxicity toward RPE1 cells. Quantitative structure–activity relationship (QSAR) and docking studies supported the observed structure–activity relationships and suggested potential interactions with the ATPase binding site of DNA gyrase B. Conclusions: Triazole-conjugated 3,5-diarylidene-4-piperidones are promising multifunctional scaffolds with selective anti-S. aureus activity, antibiofilm and anti-efflux properties, and, for compound 7l, potent DNA gyrase inhibition. These findings support further optimization of this chemotype as a platform for developing antibacterial agents with polymechanistic activity. Full article

Polybenzoxazoles are promising high-performance materials for thermally stable dielectric components, microelectronic insulating layers, and aerospace-related applications owing to their exceptional thermal stability and mechanical properties; however, their poor solubility, high processing temperatures, and limited processability still restrict practical fabrication. This study presents the design and synthesis of two series of thermosetting benzoxazole monomers to address these limitations. These monomers incorporate cross-linkable arylethynyl and arylonitrile terminal groups, combined with either symmetric hexafluoroisopropylidene-bridged or asymmetric mono-benzoxazole architectures. The structure–property relationships governing solubility, curing behaviour, thermal stability, and dielectric properties are systematically investigated. The results show that incorporating hexafluoroisopropylidene units significantly enhances solubility and reduces dielectric constants, whereas nitrile-terminated systems exhibit superior thermal stability compared with their alkyne-terminated counterparts. Notably, the optimized asymmetric polybenzoxazole achieved a temperature at 5% mass loss of 602.2 °C, while the optimized symmetric polybenzoxazole exhibited an ultra-low dielectric constant of 1.83 at a frequency of 1 MHz. This work demonstrates a viable molecular design strategy for balancing solution processability, thermal stability, and dielectric performance in advanced polybenzoxazole thermosets. Full article

This study presents a quantum chemical investigation of halogen–π interactions involving halogen molecules (F₂, Cl₂, Br₂, and I₂) and a series of π-systems, including benzene, alkenes, and alkynes. Special emphasis is placed on the role of the position of the unsaturated bond (terminal vs. internal) in determining the strength and nature of these interactions. Geometry optimizations and interaction energies were calculated at the wB97X-D3/def2-TZVPP level of theory, with additional validation against CCSD(T)/CBS data. Energy decomposition analysis using SAPT0 and QTAIM analysis were also performed. The results show a clear increase in interaction strength from F₂ to I₂, with interaction energies ranging from −0.47 to −5.61 kcal/mol. The position of the double or triple bond and the local symmetry of the π-system significantly influence interaction energies, with internal and more substituted alkenes and alkynes forming stronger interactions than terminal analogs. SAPT analysis shows that halogen–π interactions are governed by a balance of electrostatic and dispersion contributions, with electrostatics representing the largest attractive term in most cases, whereas dispersion becomes increasingly important for heavier halogens and more extended π-systems and benzene. QTAIM analysis confirms the noncovalent nature of these interactions, with increasing electron density at bond critical points correlating with stronger binding. Full article

Unsaturated hydrocarbons, including alkenes, alkynes, and aromatic hydrocarbons, are important components of atmospheric volatile organic compounds (VOCs) and serve as key precursors for ozone, a major photochemical pollutant. This study aimed to characterize the sources and ozone formation potential of 29 unsaturated hydrocarbon VOCs in Beihai, a coastal city in southern China, on the basis of continuous online monitoring conducted during the summer of 2022. Continuous monitoring of unsaturated hydrocarbon VOCs in the ambient air of Beihai city during summer was conducted using a rapid online monitoring system for atmospheric VOCs. The results revealed that the total daily average concentration of unsaturated hydrocarbon VOCs was 1.21 ppbv, with an average concentration of 0.026 ppbv. The order of abundance was alkenes > aromatic hydrocarbons > alkynes. Source apportionment using the positive matrix factorization (PMF) model revealed that vehicle exhaust emissions were the primary source of unsaturated hydrocarbon VOCs in the city of Beihai, contributing 36.02%. Secondary sources included combustion sources (26.15%), solvent usage (18.55%), fuel evaporation (10.18%), and biogenic sources (9.10%). The contribution of unsaturated hydrocarbon VOCs to ozone formation was estimated using the ozone formation potential (OFP). Aromatic hydrocarbons contributed the most (51.22%), followed by alkenes (41.8%). Analysis of the diurnal variation patterns of unsaturated hydrocarbons revealed that combustion sources occurred during the night (01:00–02:00), suggesting that enhanced supervision and control measures during nighttime hours are warranted. Full article

3,6-Dihydro-2H-pyran heterocyclic framework is one of the currently developed heterocyclic building blocks in both pharmaceutical chemistry and organic synthesis, but with significant challenges. To overcome these challenges, herein, we report a robust synthetic methodology of palladium-catalyzed carboetherification of alkenes with alkynols for accessing polyfunctionalized 3,6-dihydro-2H-pyrans under aerobic oxidative conditions. In particular, this synthetic approach features excellent functional group compatibility, mild reaction conditions, and good step- and atom-economy. Additionally, an array of functional groups such as halogen group, ester, nitrile, aldehyde, phenoxy, and aromatic heterocycles were nicely tolerated, affording the synthetically challenging 2H-pyran derivatives in moderate-to-good yields. Notably, the practicability of this protocol is further verified by gram-scale synthesis and the late-stage diversification of pharmaceuticals and biologically active molecules. Full article

Background/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic activity and improve selectivity against Trypanosoma cruzi. Methods: A series of mono- and bis-triazole jatrophone derivatives was semi-synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) from a stereoselectively prepared diazido intermediate. Jatrophone, its azido precursor, and the synthesized triazole derivatives were evaluated in vitro against T. cruzi epimastigotes and intracellular amastigotes. Cytotoxicity toward mammalian host cells was assessed in parallel to determine selectivity indices. Results: Jatrophone exhibited potent activity against epimastigotes but showed poor selectivity due to significant mammalian cell toxicity. Introduction of azide and triazole functionalities altered the biological profile of the parent scaffold, leading to derivatives with reduced cytotoxicity and improved selectivity in extracellular assays. Among the evaluated compounds, a mono-triazole derivative bearing a methylene-linked cycloalkyl substituent retained antiparasitic activity while displaying markedly lower toxicity toward mammalian cells. However, in the intracellular amastigote model, most derivatives demonstrated a substantial reduction in selectivity, indicating limited translation of extracellular activity to the intracellular parasite stage. Conclusions: Triazole functionalization of the jatrophone scaffold represents a viable strategy to modulate its biological properties and reduce host-cell toxicity. Nevertheless, the reduced efficacy observed in intracellular assays underscores the limitations of epimastigote-based screening and highlights the challenges in developing selective intracellular antitrypanosomal agents from the jatrophone scaffold. Full article

Background/Objectives: The dysregulation of thiol metabolites is strongly linked to hepatocellular carcinoma (HCC) pathogenesis. However, quantifying these highly polar and oxidation-prone thiols in clinical serum samples via conventional liquid chromatography–mass spectrometry (LC-MS) remains challenging due to their poor sensitivity and reproducibility. Methods: We developed a sensitive and robust iodoacetamine-alkyne (IAM) derivatization–based LC-MS method for quantification of seven trans-sulfuration pathway thiols in human serum. Results: IAM derivatization markedly improved the method’s specificity due to enhanced chromatographic retention and diagnostic MS/MS fragments containing both the alkyne tag and analyte backbone. Sensitivity increased 33-to-160-fold versus underivatized analytes, with limits of detection of 0.02–0.1 nM. All analytes exhibited good linearity, acceptable precision with intra-day and inter-day relative standard deviations in the range of 1.2–13.8%, and high recovery from 88.6% to 102.9%. Conclusions: From the thiol quantification in human serum from 40 HCC patients and 40 healthy controls, it was found that levels of cysteine, homocysteine, glutathione, and cysteinylglycine were significantly lower in HCC patients (p < 0.05). A two-variable logistic regression model using cysteine and cysteinylglycine achieved 90.0% specificity and 80.0% sensitivity for robust HCC discrimination between HCC patients and healthy controls to some extent, with an area under the receiver operating characteristic curve of 0.88 (95% confidence interval: 0.792–0.968). Full article

A novel transition-metal-free alkyne–thiol click polymerization with 100% atom economy is reported. Using ^tBuOLi as a catalyst at 80 °C, the polymerization efficiently yields poly(vinyl sulfide)s (PVSs) with molecular weights up to 11,800 g/mol and yields up to 91%. These sulfur-rich polymers exhibit high thermal stability (T_d up to 293 °C) and high refractive indices (1.8375–1.6383) across the visible range. By integrating abundant sulfur coordination sites with aggregation-induced emission (AIE) properties, the PVS aggregates serve as high-performance fluorescent chemosensors. The sensor enables exclusive, sensitive trace detection of Pd²⁺ and Au³⁺ with remarkable anti-interference capability and pH robustness (pH 1–7). Notably, an ultrafast response (1–2 min) for Pd²⁺ is achieved, with limits of detection (LOD) reaching 7.11 × 10⁻⁷ M for Pd²⁺ and 1.06 × 10⁻⁶ M for Au³⁺, and corresponding limits of quantification (LOQ) reaching 2.37 × 10⁻⁶ M and 3.53 × 10⁻⁶ M, respectively. This methodology offers a sustainable route to heteroatom-rich macromolecules for next-generation optical engineering and environmental monitoring. 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

A convergent scheme for the preparation of conjugates with the dispiroindolinone-pyrrolidine-thioimidazolone and glutarimide moieties connected via a triazole-containing linker is proposed. Target conjugates were synthesized by azide–alkyne (3+2) cycloaddition reactions between propargylthio-substituted dispiroindolinone-pyrrolidine-imidazolones and an azido-glutarimide derivative. The starting compounds were available isothiocyanates, glycine, substituted benzaldehydes, chloroacetamide, and ethyl acrylate. The key azide–alkyne (3+2) cycloaddition step was carried out using TBTA as a catalyst, achieving >70% product yields. The resulting bifunctional compounds contained a fragment of dispiroindolinone (a p53-MDM2 interaction inhibitor) and glutarimide, a ubiquitin ligase ligand. The obtained dispiroindolinone-glutarimide conjugates were tested for their potential as hetero-PROTAC compounds for p53 reactivation. Individual conjugates showed preferential cytotoxicity against HCT116 colon carcinoma cells (wild-type53) compared to the isogenic HCT116p53^−/− subline. Full article

Despite substantial reductions in precursor emissions, persistent summer ozone (O₃) pollution remains a critical environmental challenge in the North China Plain. This study integrated O₃ and volatile organic compound (VOC) data from the summers of 2014–2020 with an observation-based box model (OBM) to analyze O₃ pollution trends, VOC composition, sources, and sensitivity in Zhengzhou. The results indicated a continuous intensification of summer O₃ pollution, a progressive annual increase in polluted days, and an average annual concentration increase of 6.72 μg m⁻³ yr⁻¹. Further, the average VOC concentration on polluted days was 11.7% higher than that on non-polluted days, with alkanes dominating the component distribution, followed by aromatic hydrocarbons, alkenes, and alkynes. Subsequently, a source-apportionment model (positive matrix factorization) was used to identify six VOC sources: motor vehicle emissions (28.4%), industrial emissions (23.2%), solvent use (16.0%), liquefied petroleum gas/natural gas use (15.8%), fuel combustion (11.4%), and biological sources (5.4%). The photochemical age method corrected VOC loss during atmospheric transport, revealing that the traditional O₃-formation potential (OFP) method underestimated the contributions of alkenes and aromatic hydrocarbons, with isoprene, m/p-xylene, and ethylene as key species. Furthermore, multi-scenario simulations showed that solely reducing nitrogen oxides (NO_x) emissions caused an O₃ concentration rebound, while a 4:1 VOC to NO_x reduction ratio provided optimal control. By identifying the causal drivers of O₃ pollution in Zhengzhou, this study provides a scientific basis for designing precise emission-reduction strategies applicable to the North China Plain and analogous urban regions. Full article

In this study, a simple and efficient method for the synthesis of conjugates of N-acyl derivatives of 3,5-bis(benzylidene)-4-piperidones and phenothiazine was developed. The method was based on the acylation of 3,5-bis(benzylidene)-4-piperidones with chloroacetic acid chloride, followed by treatment of the product with sodium azide and an azide-alkyne [3+2] cycloaddition reaction between the resulting azide and 10-(prop-2-yn-1-yl)-10H-phenothiazine in the final step. Using this method, a series of seven compounds 23–29 were synthesized. The structure of synthesized compounds 23–29 was studied using ¹H, ¹³C, and ¹⁹F NMR spectroscopy and ESI-MS mass spectrometry. The cytotoxicity of compounds 23–29 and their hydrochloride salts 30–36 towards pancreatic adenocarcinoma Panc-1, bladder cancer T-24, glioblastoma T98G, breast adenocarcinoma BT-20, and normal dermal fibroblast DF-1 cells was studied using an MTT assay. Compound 29, containing 3,4,5-trimethoxyl radicals at the aromatic ring, and its hydrochloride salt 36, demonstrated the best cytotoxicity against Panc-1, T-24, T98G, and BT-20 cancer cells. Hydrochloride salts were found to exhibit superior cytotoxicity against Panc-1, T-24, T98G, and BT-20 cancer cells compared to the original 3,5-bis(benzylidene)-4-piperidones and free bases. Selective cytotoxic action against Panc-1, T-24, T98G, and BT-20 cancer cells compared to normal DF-1 cells was also observed for all the obtained compounds and their salts. Full article

Six 1,4-disubstituted pyrazoles linked to a benzenesulfonamide and a benzodioxane unit have been synthesized through a copper(I)-catalyzed formal [3+2] cycloaddition (32CA) reaction of alkynes with 3-arylsydnones. The Cu-catalyzed sydnone–alkyne cycloaddition (CuSAC) procedure has been optimized to promote the formation of the pyrazole ring and to deliver in three steps the six target compounds 5a–f, fully characterized by ¹H/¹³C-NMR and mass spectrometry (EIMS). Ten solvent conditions were evaluated. The reaction proceeded most efficiently in the presence of copper(II) sulfate pentahydrate in aqueous t-butanol in the presence sodium acetate, to reach a yield of 96%. The mechanism of the Cu(I)-catalyzed reaction has been studied within the Molecular Electron Density Theory (MEDT). This rection is a domino process that consists in a Cu(I)-catalyzed formal [3+2] cycloaddition followed of an extrusion of CO₂ yielding the final pyrazole. The capacity of heterocyclic compounds 5a–f to interact with human cyclophilin A (Cyp A), which is a host cofactor for hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), and with the HIV-1 protein gp120-CD4 was evaluated using molecular docking. Compounds 5a,b,d,f showed a satisfactory protein binding capacity. The physicochemical and metabolic properties of the compounds were also evaluated in silico. These predictions provide important information to guide future design in this series of potential antiviral agents. Full article

Gold(I) complexes are particularly useful as catalysts in a variety of reactions including, in particular, the electrophilic activation of alkyne substrates, yet they generally require the addition of a silver salt to activate the gold complex by removing an anionic ligand. This results into higher costs and possible problems related to the non-innocence of the silver additive. In this contribution, we highlight the possibility to proficiently use a dinuclear monocationic gold(I) complex developed in our laboratory as a silver-free catalyst. The complex, featuring a bridging N-phosphanyl-N-heterocyclic carbene (NHCP) ligand, indeed exhibits notable activity and selectivity in standard alkyne hydroamination and hydroalkoxylation reactions, particularly in the case of internal alkynes and secondary aromatic amines as substrates. Full article

Donor human milk (DHM) provided by human milk banks is considered the optimal feeding alternative to mother’s own milk for premature or medically compromised infants. Before distribution, DHM is subjected to Holder pasteurization (HoP) by milk banks to eliminate potential pathogens. In this study, FT-IR, GC and GC-MS were applied to characterize changes in the volatile organic compounds (VOCs) and lipid components of human milk (HM) samples that were treated by HoP. FT-IR analysis revealed changes in specific band regions, indicating modifications to triglycerides and fatty acid (FA) organization and possible disruption of the milk fat globule membrane. There was also an increase in ester groups, suggesting that HoP increases lipid oxidation. GC analysis showed a reduction in long-chain FAs, including certain omega-3 and omega-6 polyunsaturated FAs (PUFAs). GC-MS analysis showed that HoP-treated samples contained higher levels of alkanes, aldehydes, aromatics and ketones than raw HM. Conversely, other compounds, including furans, and alkynes, were found exclusively in pasteurized HM. These results show that HoP affects the lipid and VOC components of HM, highlighting the need for research into alternative pathogen elimination strategies in human milk bank practices. Full article