Search Results (222)

4,4′-substituted-2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bisphenols (1a–d) and 2,6-bis{[3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substitutedphenols (2a–b) were synthesized via microwave (MW) irradiation of aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.^8,170.^2,70.^11,16]icosane 2 with p-substituted phenols. Microwave (MW) irradiation improved reaction rates and yields at 80 °C. Compounds 1a–d were racemic, and 2a–b were diastereomeric. NMR spectra revealed key signals for the perhydrobenzimidazole fragment, aromatic rings, and aminal carbons. Differences in the ¹³C NMR spectra highlighted structural variations, such as distinct carbonyl and methoxyl signals in 2d. MW irradiation at higher temperatures (100–120 °C) reduced yields of 1, especially for phenols with methyl (Me) and methoxy (OMe) groups, suggesting a shift toward the formation of compound 2. Additionally, higher temperatures led to polymerization byproducts, emphasizing the impact of MW energy on reaction pathways. These results provide valuable insights for designing molecules with potential applications in materials science and medicinal chemistry. Full article

A texture-modifying food matrix (MPS) was obtained by micronizing apple cell polysaccharides and adding spray-dried low-methoxy pectins. This study aimed to demonstrate the effect of MPS addition on a versatile group of products, including instant soup, salad dressing, buttermilk, tomato juice, apple juice, and instant kissel. The rheological properties of suspensions with two MPS concentrations added to these products were compared with those of the control. Additionally, the water holding and retention capacity, swelling capacity, and wetting angles of the MPS and its components were characterized to determine the technological properties of these products. Results show that the MPS proportionally increases viscosity and the thixotropic effect of all studied products, except buttermilk, in relation to concentration. In particular, very pronounced effects were obtained for apple, tomato juice, and salad dressing. All studied suspensions were classified as pseudoplastic fluids; the addition of MPS resulted in varying changes in pseudoplasticity, depending on the product. In summary, this study showed that MPS, as a natural and rich source of dietary fibre matrix, effectively alters rheological properties and may therefore be considered a substitute for other food additives currently used in the food industry. Full article

Type 2 diabetes mellitus (T2DM) remains a global health challenge, prompting the development of novel α-glucosidase inhibitors (AGIs) to regulate postprandial hyperglycemia. This study reports the design, synthesis, and evaluation of indole-based Schiff base derivatives (4a–j) bearing a fixed methoxy group at the C₅ position. This substitution was strategically introduced to enhance lipophilicity, electronic delocalization, and π-stacking within the enzyme active site. Among the series, compound 4g (3-bromophenyl) exhibited the highest inhibitory activity (IC₅₀ = 10.89 µM), outperforming the clinical reference acarbose (IC₅₀ = 48.95 µM). The mechanism was supported by in silico analyses, such as the Density Functional Theory (DFT), molecular electrostatic potential (MEP) mapping, and molecular dynamics simulations, and CNN-based docking revealed that 4g engages in stable hydrogen bonding and π–π interactions with key residues (Asp327, Asp542, and Phe649), suggesting a potent and selective mode of inhibition. In silico ADMET predictions indicated favorable pharmacokinetic properties. Together, these results establish C₅–methoxy substitution as a viable strategy to enhance α-glucosidase inhibition in indole-based scaffolds. Full article

This study aimed to investigate the glycaemic control potential and modulation of GABA-induced chloride currents (I_GABA) of H. revolutum and the possible bioactive xanthones. Fractions from the leaf and stem extracts (dichloromethane and methanol) were assessed for in vitro α-glucosidase-inhibitory potential and their ability to modulate I_GABA (GABAergic effect) through GABA_A receptors heterologously expressed in Xenopus oocytes. Xanthones 4-hydroxy-2,3-dimethoxy-9H-xanthen-9-one (1), 3-hydroxy-2,4-dimethoxy-9H-xanthen-9-one (2) and trans-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-5-methoxy-2,3-dihydro-7H-[1,4]dioxino[2,3-c]xanthen-7-one (3) were isolated from the stem and tested in the GABA_A receptors assay, but only 3 was assessed for α-glucosidase-inhibitory action. Compared to acarbose (IC₅₀ = 6.16 µM), 3 showed a mild to moderate α-glucosidase-inhibitory activity (IC₅₀ = 45.1 µM), which may be attributed to the absence of a hydroxyl group at its xanthone core. Isomeric compounds 1 and 2 significantly enhanced I_GABA with similar efficacy, while 3 was inactive, which may be attributed to its notable structural difference (cyclic ether substitution) compared to compounds 1 and 2. H. revolutum stem contains xanthones with α-glucosidase-inhibitory potential, which also enhance I_GABA and could be further studied as a medicinal plant for managing GABA_A receptor-mediated mental disorders and/or diabetes. Full article

The photochemistry of 1,3,4-oxadiazoles remains poorly understood, despite their recognized importance in medicinal chemistry and materials science. In this work, we report a detailed matrix-isolation study of 2-amino-5-(4-methoxyphenyl)-1,3,4-oxadiazole, combining low-temperature infrared spectroscopy with broadband UV photolysis and quantum chemical calculations. Theoretical analysis predicts the gas-phase molecule to exist exclusively as the amino tautomer, populating two nearly isoenergetic conformers (anti and syn) defined by the relative orientation of the amino and methoxy groups. Experimental IR spectra of the compound isolated in Ar and Xe matrices at 15 K confirm sole trapping of the amino tautomer. Annealing of the Xe matrix to the highest achievable temperature induced no detectable spectral changes, consistent with the predicted isoenergetic character of the conformers. Upon broadband UV irradiation (λ > 200 nm), the compound undergoes ring opening through N−N and C−O bond cleavages, paralleling the behavior of unsubstituted 1,3,4-oxadiazole system. Isocyanates emerge as the predominant photoproducts from these photochemical pathways. Additionally, spectroscopic evidence supports an alternative reaction pathway involving early-stage amino−imino tautomerization, followed by ring-opening of the imino tautomer through isocyanic acid extrusion, leading to the formation of a nitrilimine intermediate. This reactive species subsequently photorearranges into a carbodiimide via a diazirine-mediated pathway. All photoproducts were unambiguously identified through their distinct IR signatures, supported by quantum chemical calculations and reference data from structurally related systems. These findings provide unprecedented insight into the photochemical behavior of substituted 1,3,4-oxadiazoles and unveil new reaction pathways modulated by substituent effects, expanding the understanding of their photoreactivity. Full article

Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of ten hybrid indolyl-methylidene phenylsulfonylhydrazones and one bis-indole derivative were designed, synthesized, and structurally characterized using NMR and high-resolution mass spectrometry (HRMS). Prior to synthesis, in silico screening was performed to assess drug likeness and ADME-related properties. Single-crystal X-ray diffraction was conducted for compound 3e. The cytotoxic potential of the synthesized compounds was evaluated using the MTT assay against MCF-7 (ER-α⁺) and MDA-MB-231 (triple-negative) breast cancer cell lines. Additionally, quantitative structure–activity relationship (QSAR) analysis was conducted to identify key structural features contributing to activity. Results: Most compounds exhibited selective cytotoxicity against MCF-7 cells. Notably, compound 3b demonstrated the highest potency with an IC₅₀ of 4.0 μM and a selectivity index (SI) of 20.975. Compound 3f showed strong activity against MDA-MB-231 cells (IC₅₀ = 4.7 μM). QSAR analysis revealed that the presence of a non-substituted phenyl ring and specific indolyl substituents (5-methoxy, 1-acetyl, 5-chloro) significantly contributed to enhanced cytotoxic activity and ligand efficiency. Conclusion: The synthesized phenylsulfonylhydrazone hybrids exhibit promising and selective cytotoxicity, particularly against ER-α⁺ breast cancer cells. Structural insights from QSAR analysis provide a valuable foundation for the further optimization of this scaffold as a potential source of selective anticancer agents. Full article

The capitula of Chrysanthemum indicum Linné or C. morifolium Ramatuelle (Kikuka in Japanese) are included in several formulae of Kampo medicines (traditional Japanese medicines), such as Chotosan, which is used for headache and dizziness. Luteolin, the principal constituent of C. indicum, has antioxidant and anti-inflammatory activities. However, the effects of other flavonoids on this crude drug have not yet been thoroughly investigated. To evaluate and compare anti-inflammatory effects, we used primary cultured rat hepatocytes, which produce proinflammatory mediators, such as nitric oxide (NO) and proinflammatory cytokines, in response to interleukin (IL)-1β. Eight derivatives of 5,7-dihydroxyflavone were purified and identified in the ethyl acetate-soluble fraction of a C. indicum capitulum extract: luteolin (Compound 1), apigenin (2), diosmetin (3), 5,7-dihydroxy-3′,4′,5′-trimethoxyflavone (4), acacetin (5), eupatilin (6), jaceosidin (7), and 6-methoxytricin (8). Luteolin is the most abundant compound in this fraction. All compounds significantly suppressed NO production in hepatocytes, with apigenin and acacetin showing the greatest efficacy. The comparison of the IC₅₀ values of the inhibition of NO production suggests that substitutions by hydroxyl and methoxy groups at the C-3′ and C-4′ positions of 5,7-dihydroxyflavone may be at least essential for the suppression of NO production. In hepatocytes, acacetin and luteolin decreased the levels of mRNAs encoding inducible nitric oxide synthase (iNOS), proinflammatory cytokines, including tumor necrosis factor, IL-6, and type 1 IL-1 receptor, which regulates inflammatory responses. Based on the comparison of the IC₅₀ values and the content, luteolin, jaceosidin, and diosmetin may be responsible for the anti-inflammatory effects of C. indicum capitula. Full article

A series of new isatin hydrazones bearing phosphorus-containing moiety was synthesized through a simple, high-yield and easy work-up reaction of phosphine oxide (Phosenazide) or phosphinate (2-chloroethyl (4-(dimethylamino)phenyl)(2-hydrazinyl-2-oxoethyl)phosphinate, CAPAH) hydrazides with aryl-substituted isatins. The ³¹P NMR technique showed that, in most cases, out of 12 examples in solution, the ratio of the two spatial isomers varied from 1:1 to 1:3. Quantum chemical calculations confirmed the predominance of Z,syn form both in the gas phase and in solution. According to X-ray analysis data in crystals, they exist only in Z,syn form too. Most of the phosphine oxide derivatives and 5-methoxy- and 5-bromoaryl phosphinate analogs exhibit anti-aggregant activity at the level of acetylsalicylic acid but inhibit platelet activation processes more effectively. The 5-chloro type phosphinate derivative exhibits anti-aggregant properties more effectively than acetylsalicylic acid under the conditions of the tissue factor (TF)-activated thromboelastography (TEG) model, the ex vivo thrombosis model. Thus, all the obtained results can become the basis for future pharmaceutical developments to create effective anti-aggregation drugs with broad antithrombotic potential. Full article

Methoxycamalexins are close structural derivatives of the indolic phytoalexin Camalexin, which is a well-known drug lead with an antiproliferative and antioxidant profile. 6-methoxycamalexin, 7-methoxycamalexin, and 6,7-dimethoxycamalexin are natural bioactive products, and there is significant interest in the development of efficient methods for the synthesis of structurally related analogues. Herein, we describe an efficient and high-yielding method for the synthesis of variously substituted hydroxy-, bezyloxy, and methoxycamalexins. A set of methoxy-, hydroxy-, and benzyloxy-indoles were successfully amidoalkylated with N-acyliminium reagents derived in situ from the reaction of thiazole or methylthiazoles with Troc chloride. Eleven novel N-acylated analogues were synthesized, with yields ranging from 77% to 98%. Subsequent oxidative reactions with o-chloranil or DDQ led to 10 novel oxy-camalexins in 62–98% yield. This two-step approach allowed the synthesis of two 4,6-dimethoxy camalexins, which are difficult to obtain using published methods. The structure of the obtained products was unequivocally determined by ¹H-, ¹³C{¹H}-, HSQC-NMR, FTIR, and HRMS spectral analyses. An in silico assay was carried out on the obtained products to assess their general toxicity and physicochemical properties, including their compliance with Lipinski’s rule of five. The results indicate that all compounds have good potential to be developed as drugs or agrochemicals. Full article

Apomorphine (APO), a dopamine agonist, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts antioxidant effects, making it a promising candidate for neuroprotection against oxidative stress. This study evaluated neuroplasticity-enhancing properties of newly synthesized APO derivatives, focusing on their ability to promote neurite outgrowth in PC12 cells under nerve growth factor (NGF) stimulation. D55, an APO derivative, retains the hydroxyl group at APO’s 11th position while substituting the 10th with an ethoxy group. D55 exhibited the highest potency (EC₅₀ = 0.5661 nM), significantly enhancing neurite outgrowth. APO demonstrated the highest efficacy (Emax ~10-fold increase), while edaravone (Eda) required higher concentrations (EC₅₀ = 22.5 nM) for moderate effects (Emax ~4-fold increase). D30, in which the 11th hydroxyl was replaced with a methoxy group, had no effect. Neurite outgrowth-promoting effects of APO, D55, and Eda were significantly attenuated by Nrf2 siRNA knockdown, confirming that their neuroplasticity effects are Nrf2-mediated. These findings confirm that D55 is a highly potent Nrf2-activating compound with strong neuroprotective potential, providing new insights into its therapeutic applications for neurodegenerative diseases associated with oxidative stress. Full article

This study describes the synthesis of O-alkylated benzaldehydes 1–8, Schiff bases 9–28, and benzoxazole derivatives 29–48 using microwave, ultrasound, and mechanochemical reactions, as well as reactions in deep eutectic solvents in excellent yields, and their antiproliferative and antibacterial activities. The in vitro evaluation of antiproliferative activity for the newly synthesised benzoxazole derivatives 29–48 against a diverse panel of human cancer cell lines, such as LN-229, Capan-1, HCT-116, NCI-H460, DND-41, HL-60, K-562, and Z-138 demonstrated that the majority of these benzoxazole derivatives displayed promising anticancer activity, particularly against non-small cell lung cancer (NSCLC) cells (NCI-H460). Notably, several derivatives showed enhanced activity compared to the included reference drug, etoposide. Considering the influence of substituents at position 5 of the benzoxazole ring and positions 3 and 4 of the phenyl ring on the antiproliferative activity, it is evident that derivatives 41–48 bearing a methoxy group at position 3 generally exhibit higher activity compared to compounds 29–40, which lack substitution at position 3. Furthermore, derivatives substituted at position 4 with a morpholine substituent, as well as those with an N,N-diethyl group, exhibited higher activity compared to other evaluated benzoxazole derivatives. The in vitro antibacterial evaluation against Gram-positive and Gram-negative bacteria revealed that benzoxazole derivative 47 exhibited notable activity, against the Gram-negative bacterium Pseudomonas aeruginosa (MIC = 0.25 μg/mL) and the Gram-positive bacterium Enterococcus faecalis (MIC = 0.5 μg/mL). The results point out that this class of benzoxazoles can be efficiently synthesized using eco-friendly methods and represent promising candidates for further design and optimization aimed at developing potent antiproliferative agents. Full article

Background: Lipid nanoparticles (LNPs) have proven effective in delivering RNA-based modalities. Rapid approval of the COVID-19 vaccines highlights the promise of LNPs as a delivery platform for nucleic acid-based therapies and vaccines. Nevertheless, improved LNP designs are needed to advance next-generation vaccines and other gene therapies toward greater clinical success. Lipid components and LNP formulation excipients play a central role in biodistribution, immunogenicity, and stability. Therefore, it is important to understand, identify, and assess the appropriate lipid components for developing a safe and effective formulation. Herein, this study focused on developing a novel Polysorbate-80 (PS-80)-based LNP. We hypothesized that substituting conventional linear PEG-lipids with PS-80, a widely used, biocompatible injectable surfactant featuring a branched PEG-like structure, may change the LNPs biodistribution pattern and enhance long-term stability. By leveraging PS-80’s unique structural properties, this study aimed to develop an mRNA-LNP platform with improved extrahepatic delivery and robust freeze/thaw tolerance. Methods: We employed a stepwise optimization to establish both the lipid composition and formulation buffer to yield a stable, high-performing PS-80-based SARS-CoV-2 mRNA-LNP (SC2-PS80 LNP). We compared phosphate- versus tris-based buffers for long-term stability, examined multiple lipid ratios, and evaluated the impact of incorporating PS-80 (a branched PEG-lipid) on in vivo biodistribution. Various analytical assays were performed to assess particle size, encapsulation efficiency, mRNA purity, and in vitro potency of the developed formulation and a humanized mouse model was used to measure its immunogenicity over six months of storage at −80 °C. Results: Replacing the standard 1,2-dimyristoyl-rac-glycero-3-methoxy polyethylene glycol-2000 (PEG-DMG) lipid with PS-80 increased spleen-specific expression of the mRNA-LNPs after intramuscular injection. Formulating in a tris-sucrose-salt (TSS) buffer preserved the LNP’s physicochemical properties and in vitro potency over six months at −80 °C, whereas a conventional PBS-sucrose (PSS) buffer was less protective under frozen conditions. Notably, TSS-based SC2-PS80 LNPs elicited potent humoral immunity in mice, including high anti-spike IgG titers and robust pseudovirus neutralization, comparable to freshly prepared formulations. Conclusions: A PS-80-based mRNA-LNP platform formulated in TSS buffer confers improved extrahepatic delivery, long-term frozen stability, and strong immunogenicity against SARS-CoV-2 following six months. These findings offer a promising pathway for the design of next-generation mRNA vaccines and therapeutics with enhanced stability and clinical potential. Full article

The use of CO₂ as a C1 carbon source for the synthesis of valuable chemicals through biotechnology methods represents an effective strategy to fix carbon dioxide. Phenolic acid decarboxylases possess the capability to introduce a carboxyl group into para-hydroxystyrenes for the regionally selective synthesis of (E)-para-hydroxycinnamic acids, utilizing bicarbonate as a CO₂ source. It is difficult to achieve this reaction with traditional chemical methods, and only a few enzymes have been isolated and characterized. Here, we mined which low amino acid sequence shared its identity with those of related decarboxylases and which heterologously expressed phenolic acid decarboxylase PAD_Cs from Clostridium sp. DSM 8431 in E. coli. The recombinant PAD_Cs displayed maximum activity at 50 °C, and pH 5.0. PAD_Cs showed distinct carboxylation ability. The carboxylated substrates have a wide range of substitution modes on aromatic systems, including alkyl and alkoxy groups as well as halogens. Furthermore, the carboxylation conversion rates were impressive: para-hydroxystyrene exceeded 20% and 2-methoxy-4-vinylphenol surpassed 26%. This study indicated that PAD_Cs might serve as a potential enzyme source in biotechnological CO₂ fixation. Full article

The substituent effect has a significant influence on the optical properties of spectral shape, width, and wavelength, and the intensities of the maximum peaks of emission (EMI) and circularly polarized luminescence (CPL). In this work, we conducted a systematic theoretical study to investigate how substituents alter the optical response in the EMI and CPL spectra of three [7]helicene derivatives at the vibronic level. To incorporate the vibronic effect, a state-of-the-art time-dependent (TD) method was used to achieve the fully converged spectra. In the meantime, a time-independent (TI) approach also provided a way to show the progression of the spectra, serving as a complementary strategy and creating reliable documentation for the experiment. The experimental spectra of EMI and CPL are nicely reproduced, which validates the reliability of the Adiabatic Hessian (AH) model in simulating experimental data. This allowed us to analyze in detail the effect of substituents, particularly on the optical responses. The introduction of cyano and methoxy groups is highlighted, as they altered the transition dipole moments and led to a 1000-fold increase in the intensity of EMI and CPL. Moreover, substituents can also rationally alter the spectral shape of EMI and CPL by affecting the responsible normal modes. The unique CN stretching and the MeO rotation in the substituted [7]helicene are highlighted as key factors contributing to the different behaviors of EMI and CPL. This sheds light on the design and synthesis of helicenes that can serve as ideal full-color EMI and CPL emitters. Full article

Substituted phenols, including chlorophenols, are important analytes, particularly in the context of environmental analysis. Chlorophenols are formed during the disinfection of drinking water by chlorination and are important water pollutants. Gas chromatography–mass spectrometry (GC-MS) is an important method for the analysis of chlorophenols. Retention indices are used in GC-MS analysis to improve the accuracy of identification. Our research reveals that the retention indices currently available for substituted phenols are erroneous in a number of cases. We report reliable retention index values for pentafluorophenol, 5-methoxy-2-nitrophenol, 4-cyanophenol (stationary phase: 5%-phenyl-polymethylsiloxane), 3-methoxyphenol, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol, 2,3-dichlorophenol, 2,5-dichlorophenol, 2,6-dichlorophenol, 3,4-dichlorophenol, 3,5-dichlorophenol, 2,3,5-trichlorophenol, 2,3,6-trichlorophenol, 2,4,5-trichlorophenol, and 2,4,6-trichlorophenol (stationary phase: polyethylene glycol modified with 2-nitroterephthalic acid). The structures of the standard samples were confirmed, and measurements were performed under various conditions. The analysis of the causes of the incorrect records appearing in the well-known NIST database was also carried out. Full article