Search Results (154)

1,2-Benzothiazine derivatives have attracted attention as structurally versatile scaffolds for antiviral drug discovery. Their sulfur-containing heterocyclic core supports diverse substitution patterns, allowing modulation of physicochemical properties and biological activity through medicinal chemistry optimization. This review summarizes published studies on 1,2-benzothiazine-based derivatives as potential inhibitors of human immunodeficiency virus (HIV) and hepatitis C virus (HCV), with particular emphasis on structure–activity relationships (SAR). Comprehensive SAR analyses indicate that substitutions at the N-1 and C-3 positions play a pivotal role in modulating antiviral potency and selectivity. Among the reported compounds, the most selective anti-HIV agent was a pyrazole-substituted 1,2-benzothiazine (9h) bearing a 2-amino-4-methylthiazolehydrazidoacetyl moiety, which exhibited an EC₅₀ value of 3.8 μM against HIV-1 in primary human peripheral blood mononuclear cells. For HCV, the most promising derivative was a pyrazolebenzothiazine (5b) containing a 4-chloro substituent in the N-1 phenyl ring and a p-methanesulfonamidophenyl group at the C-3 position, demonstrating an IC₅₀ value of 7.9 μM in the NS5B polymerase assay. Despite showing antiviral activity against both HIV and HCV, all tested compounds, including the most active derivatives, were considerably less potent than the corresponding reference drugs. Further optimization is therefore needed to improve their antiviral potency. Full article

Reaction of 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile with sodium 2-aminophenolate (1.5 equiv.) in anhydrous THF at ca. 0–20 °C afforded the known 4-chlorobenzo[5,6][1,4]oxazino[2,3-c][1,2,6]thiadiazine in 76% yield. In contrast, treatment of the same substrate with 2-aminophenol (3 equiv.) in acetonitrile at ca. 20 °C gave 5-cyano-7-(2-hydroxyphenyl)-4-[(2-hydroxyphenyl)amino]pyrrolo[2,3-c][1,2,6]thiadiazin-6(7H)-iminium chloride hydrate in 93% yield. This compound was characterized by ¹H and ¹³C NMR, IR and UV-vis and mass spectrometry, together with melting point and elemental analysis, and its structure was supported by single-crystal X-ray crystallography. Full article

Background/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections. Full article

Inflammasomes are central mediators of innate immune defense but can also drive pathological inflammation and pyroptotic cell death in numerous diseases. While several small-molecule inhibitors have been described, many selectively target individual inflammasomes or act through the adaptor protein ASC, leaving ASC-independent pathways unaffected. We previously identified thiomuscimol as a broad-spectrum inflammasome inhibitor that blocks both ASC-dependent and ASC-independent activation, although the structural basis for this activity remains unclear. Here, we examined the structure–activity relationship of thiomuscimol using related compounds and synthetic analogs. In primary macrophages, inflammasome activation and pyroptosis were assessed by live cell imaging of ASC speck formation, gasdermin D-mediated dye uptake, and cellular ATP levels. Structurally related sulfur-containing molecules, including taurine and isothiazole, failed to inhibit inflammasome activation, indicating that neither the sulfur in an electron-rich environment nor the heterocyclic scaffold confer activity. Replacement of the primary amine with a carbonyl group abolished activity, whereas substitution with a secondary amine preserved inhibitory potency comparable to thiomuscimol. Incorporation of the amine into an annulated piperidine ring reduced potency and revealed sensitivity to the precise positioning of the amine within the ring. Together, these findings identify key structural features required for thiomuscimol-mediated inflammasome inhibition and provide a framework for future studies to define its mechanism of action and guide the development of improved inhibitors. Full article

Imidazo [2,1-b][1,3]thiazines and their fused analogues are an important class of nitrogen- and sulfur-containing heterocycles that exhibit a wide range of biological activities. Herein, a straightforward synthetic protocol for 2,3-dihydro-5H-imidazo [2,1-b][1,3]thiazin-5-one under catalyst-free, mild conditions is reported. The title compound was obtained via the regioselective heterocyclization of 4,5-dihydro-1H-imidazole-2-thiol with alkyl propiolates (methyl or ethyl) by stirring at room temperature for 24 h in ethanol. The structure of the synthesized compound and the regioselectivity of the reaction were confirmed through a combination of ¹H, ¹³C, and 2D NMR experiments (HSQC, HMBC), LC-MS, and elemental analysis. The synthesized title compound is of interest to synthetic organic and medicinal chemistry as a starting building block with potential for further core modification. Full article

Background/Objectives: The development of multifunctional small molecules capable of simultaneously addressing cancer progression and antimicrobial resistance represents an important challenge in medicinal chemistry. This study aimed to design, synthesize, and biologically evaluate a series of novel morpholine-based nitrogen-rich heterocyclic hybrids as potential anticancer and antibacterial agents, supported by computational investigations. Methods: Twelve morpholine-derived nitrogen-enriched heterocyclic hybrids incorporating pyran, triazine, pyrimidinone, and sulfur-containing scaffolds were synthesized and fully characterized using IR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Their antiproliferative activities were evaluated against MCF-7 and HCT-116 cancer cell lines. The most active compounds were further investigated through kinase inhibition assays, cell cycle analysis, apoptosis, mitochondrial membrane potential, intracellular ROS determination, and apoptosis-related gene expression. Antibacterial, antibiofilm, antioxidant, and computational studies, including molecular docking, molecular dynamics simulations, MM-GBSA/MM-PBSA binding free-energy calculations, DFT calculations, and ADMET prediction, were also performed. Results: Compounds 3, 10, and 12 exhibited the highest antiproliferative activity, with compound 10 emerging as the lead candidate. It potently inhibited EGFR, PI3K, and mTOR, with IC₅₀ values of 0.086 ± 0.003, 0.107 ± 0.005, and 0.223 ± 0.008 μM, respectively. Mechanistic investigations revealed G₂/M arrest in MCF-7 cells and G₀/G₁ arrest in HCT-116 cells, accompanied by apoptosis rates of 32.66% and 37.12%; mitochondrial membrane depolarization; a 3.55-fold increase in intracellular ROS; upregulation of caspase-3, caspase-9, and Bax; and downregulation of Bcl-2, supporting activation of the intrinsic apoptotic pathway. Compound 10 also displayed the broadest antibacterial spectrum, surpassed ciprofloxacin against several tested isolates, exhibited MIC values of 5–20 μg/mL, achieved 42.80% inhibition of Pseudomonas aeruginosa biofilm formation, and showed the strongest antioxidant activity in DPPH and ABTS assays. Computational analyses supported the experimental findings by predicting stable interactions with EGFR and Staphylococcus aureus DNA gyrase, together with favorable MM-GBSA/MM-PBSA binding free energies of −23.44 and −24.99 ± 2.71 kcal/mol, respectively. Conclusions: The present findings identify compound 10 as a promising multifunctional lead with potent anticancer, antibacterial, antibiofilm, antioxidant, and multitarget kinase inhibitory activities. The combined biochemical, cellular, and computational findings support the proposed involvement of the EGFR/PI3K/mTOR signaling pathway in its antiproliferative activity and identify DNA gyrase as a potential antibacterial target. Nevertheless, the present study is limited to in vitro biological evaluation and computational investigations. Therefore, further in vivo efficacy studies, pharmacokinetic profiling, toxicity assessment, and experimental validation of the proposed molecular targets are warranted before considering preclinical development. Full article

Thermochemical conversion of nitrogen- and sulfur-rich biomass-derived wastes, such as sewage sludge, algae, and agricultural residues, is a promising route for renewable fuel production and waste valorization. However, fuel-bound nitrogen can be released as NH₃, HCN, and HNCO, while sulfur species such as H₂S, SO₂, and COS accelerate catalyst deactivation and generate NO_x/SO_x precursors. Metal-loaded ZSM-5 catalysts are attractive for clean catalytic pyrolysis because they combine the MFI pore confinement and tunable Brønsted/Lewis acidity of ZSM-5 with the hydrogen transfer, dehydrogenation, cracking, redox, and sulfur-tolerance functions of metal species. This review critically summarizes recent advances in metal-loaded ZSM-5 catalysts for catalytic denitrogenation of biomass-derived solid wastes. The formation and migration of NH₃, HCN, HNCO, tar-N, and char-N are first discussed to clarify the chemical basis of fuel-N conversion. The effects of ZSM-5 pore structure, acid-site distribution, Si/Al ratio, hierarchical porosity, and synergy on adsorption, diffusion, C-N bond cleavage, heterocyclic-N ring-opening, aromatization, and nitrogen redistribution are then analyzed. Catalyst deactivation under realistic pyrolysis atmospheres is also highlighted, including coke deposition, metal sintering, framework dealumination, mineral poisoning, and H₂S/SO₂/COS-induced sulfur poisoning. Finally, future directions are proposed for designing multifunctional ZSM-5-based catalysts integrating denitrogenation activity, sulfur resistance, coke resistance, regenerability, and quantitative nitrogen/sulfur mass balance. Full article

Volatile sulfur compounds (VSCs) are a subgroup of plant volatile organic compounds (VOCs) that are chemically reactive and sensory-active. In tomato (Solanum lycopersicum), sulfur-containing volatiles such as methanethiol, dimethyl sulfide, dimethyl disulfide, dimethyl trisulfide, volatile thiols, and heterocyclic sulfur compounds are of particular relevance due to their extremely low odor thresholds and strong influence on aroma perception. Beyond their sensory importance, VSCs have been shown to be involved in plant defense mechanisms, stress responses, redox homeostasis, and multitrophic interactions with microorganisms, herbivores, and neighboring plants. The formation of these structures is governed by complex interactions between sulfur assimilation pathways, lipid peroxidation processes, environmental factors, and both enzymatic and non-enzymatic reactions. The accurate characterization of VSCs remains challenging due to the following factors: their high reactivity; their low abundance; their chemical instability; and their susceptibility to oxidation. Despite the significant enhancement in detection of VSC capabilities brought about by modern analytical approaches, such as gas chromatography coupled with sulfur-selective detection and high-resolution mass spectrometry, significant methodological limitations remain. This review summarizes the current state of knowledge on the analytical challenges of VSCs in tomato plants, their biosynthesis and biological functions, mainly in the context of plant defense. Full article

Anthraquinone-based intercalating compounds, such as doxorubicin and mitoxantrone, have long been used clinically due to their ability to induce DNA damage. More recently, heteroarene-fused anthraquinones have been developed to further enhance their anticancer activity. Among these compounds, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated as derivative a) was identified as a potent apoptotic inducer. Based on this scaffold, two additional derivatives were synthesized by replacing the sulfur atom within the heterocyclic ring with nitrogen (derivative b) or oxygen (derivative c). Building upon our previous identification of ENOX2 as the primary target of this scaffold, the present study investigated the antiproliferative effects and underlying mechanisms of these derivatives in colon cancer cells with varying p53 statuses. Derivatives a and b effectively induced apoptosis and suppressed proliferation in p53 wild-type HCT116 cells, which was concomitantly accompanied by significant ENOX2 downregulation and the activation of intrinsic apoptotic signaling. In contrast, p53-null HCT116 cells exhibited reduced sensitivity, attenuated apoptotic responses, and minimal ENOX2 downregulation. Notably, derivative c primarily induced G2/M arrest rather than apoptosis regardless of p53 status, indicating a predominantly cytostatic mechanism. Collectively, these findings suggest that the degree of ENOX2 modulation is linked to the distinct anti-proliferative responses induced by heteroarene-fused anthraquinones, and that p53 status serves as a critical molecular switch influencing the transition between cytostatic growth arrest and apoptotic cell death. Full article

Sulfonamides are a fundamental class of compounds with diverse pharmacological applications. Here, two benzene-1,3-disulfonamide-containing cycloalkyne compounds were designed to demonstrate the strained conformations due to the 11-membered ring. Their structures were experimentally analyzed using single-crystal X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. The molecules exhibit flexible sulfonamide conformations together with characteristic distortions of the benzene and alkyne moieties. Comparing the compound data obtained, the proton NMR chemical shift of hydrogen at the 2-position of the benzene ring shows a correlation of a dihedral angle involving the benzene ring and sulfonamide sulfur, and the carbon NMR shift suggests an angle distortion of the alkyne. The conformations of the crystal structure and the solution state in DMSO are supported by NOESY spectra and DFT calculations. The relative chemical shift differences were quantitatively reproduced by DFT calculations. We believe this fundamental research will contribute to the design and development of sulfonamide–alkyne–benzene-based medium-sized heterocyclic molecules with detailed conformation predictions. Full article

The clinical success of cisplatin has significantly spurred the exploration of new organometallic complexes in oncology. In this quest, repurposing of auranofin as an anticancer agent has diverted the research interest from platinum to gold complexes, as gold offers unique chemical features; among them, thioredoxin reductase (TrxR) inhibition is one of the most extensively studied anticancer pathways. In this study, we have compiled the major ligand modifications reported for gold(I) complexes and categorized them into various groups, which include sulfur-based ligands, nitrogen-containing heterocyclic ligands, carbon-derived ligands, and N-heterocyclic carbene-based ligands. Also, a few structurally distinct ligands, including propargyl-, allene-, tricarbene-, and urea-functionalized NHC frameworks, have further extended structural diversity and functional potential. The in vitro evaluation of these newly synthesized gold complexes against various cancer cell lines exhibited enhanced biological potential compared to conventional metal complexes. Comparative evaluation of the reported cytotoxicity data revealed distinct structure–activity relationships among different ligand classes, with phosphine-carbon donor and bis-NHC frameworks emerging as the most promising ligand for achieving potent anticancer activity, highlighting the critical role of ligand design in modulating anticancer activity. In addition, the use of bioactive pharmacophores derived from natural products and active pharmaceuticals has emerged as a promising design strategy for developing multitarget gold(I) complexes with enhanced therapeutic efficacy. Among the reviewed compounds, complex 68 containing a bis-NHC ligand exhibited the highest potency against HL-60 leukemia cells (GI₅₀ = 0.017 μM), while complex 49 bearing a carbon-donor ligand demonstrated remarkable activity against A549 lung cancer cells (IC₅₀ = 0.02 μM). Several other gold(I) complexes also exhibited submicromolar activity against diverse cancer cell lines, further emphasizing the importance of rational ligand engineering in enhancing anticancer efficacy. Collectively, gold(I) complexes have emerged as a promising class of anticancer agents, and the comparative evaluation presented herein provides a valuable framework for identifying potent ligand scaffolds and guiding the rational development of next-generation gold-based therapeutics. Future advances in ligand engineering may facilitate targeted drug delivery, controlled release, and multi-mechanistic therapeutic strategies to overcome toxicity and drug resistance while enhancing therapeutic efficacy. Full article

Thioesterification of (2E,2′E)-3,3′-(1,4-phenylene)diacrylaldehyde with thiols has been performed using a bulky N-heterocyclic carbene (NHC) as an organocatalyst. This metal-free protocol enables efficient synthesis of new mono and difunctional acrolein derivatives in high isolated yields under mild conditions. Importantly, the reaction proceeds in the absence of external additives or oxidants, and requires only low organocatalyst loadings, thereby facilitating the straightforward isolation of structurally defined sulfur-containing acrolein derivatives in both symmetric and asymmetric forms. The resulting functional acrolein derivatives are the hitherto underexplored class of functional building blocks with promising potential for biomedical materials, including drug delivery systems and other biomaterials applications. Full article

Cubane-type iron–sulfur clusters play central roles in biological nitrogen fixation, where precise redox regulation governs multi-electron transfer processes. However, how heterometal centers and terminal ligands cooperatively modulate the electronic structure and redox behavior of such clusters remains insufficiently understood. Herein, we report a systematic study on a series of cubane-type [MoFe₃S₃N] clusters as structural mimics of nitrogenase cofactors. Using [(Tp*)MoFe₃S₃(μ₃-NSiMe₃)Cl₃]⁻ as a common precursor, thiolate (RS⁻; R = Me, Et, Ph) and N-heterocyclic carbene (NHC^R; R = Me, Et, iPr) ligands were introduced to probe ligand effects under an invariant cluster framework. All complexes were fully characterized by single-crystal X-ray diffraction and electrochemical measurements. Combined with previously reported tungsten analogues, a direct comparison reveals that both heterometal identity (Mo vs. W) and terminal ligand environment significantly influence local electron density and intermetallic redox cooperativity. Notably, strong σ-donating NHC ligands and heavier heterometal centers induce distinct modulation patterns, highlighting their synergistic roles. This work provides a unified platform for disentangling metal- and ligand-driven effects and offers feasible strategies for the rational tuning of redox properties in heterometallic Fe–S clusters. Full article

The effects of ambient storage (A), cold storage (C), and frozen storage (F) on the quality, metabolomic characteristics, and sulfur-related aroma of red onion ‘Kewei Red 10’ (R10) and yellow onion ‘Kewei Yellow 14’ (Y14) were investigated using integrated non-targeted and volatile metabolomics. Ambient storage accelerated shrinkage, firmness loss, and sensory deterioration in both cultivars, whereas low-temperature storage effectively delayed quality decline. R10 exhibited better tolerance to frozen storage, while Y14 performed better under cold storage. Metabolomic analysis revealed that amino acids and lipid-related metabolites were closely associated with onion senescence in both cultivars. In contrast, flavonoids were enriched in preservation-associated subclasses in R10, whereas organic acids and their derivatives were more strongly associated with delayed senescence in Y14. Volatile metabolomic analysis identified sulfur compounds and heterocyclic sulfur compounds as the major contributors to onion aroma. Sulfur-related volatiles showed distinct cultivar-dependent accumulation patterns, with many sulfur compounds accumulating prominently in ambient-stored R10-A, whereas cold-stored Y14-C maintained relatively higher levels of characteristic onion-like aroma compounds. These findings demonstrate distinct metabolic adaptation strategies between red and yellow onions during storage and suggest that cultivar-specific storage conditions are required to optimize both shelf life and flavor quality. Full article

The in situ-generated thiocarbonyl S-methanides derived from cycloaliphatic thioketones undergo (3+2) cycloaddition onto the C=C bond of levoglucosenone yielding anticipated, polycyclic tetrahydrothiophene derivatives in a regio- and stereoselective manner. The cycloaddition process occurred stereoselectively via the less hindered exo-face approach; exo-diastereoisomers were formed in all studied reactions. Some of the obtained crystalline (3+2) cycloadducts were studied by the monocrystal X-ray diffraction analysis, which unambiguously confirmed the postulated structure. Stable (3+2) cycloadducts were isolated in good yields (50–80%). Full article