Synthesis, molecular docking and DFT analysis of novel bis-Schiff base derivatives with thiobarbituric acid for α-glucosidase inhibition assessment.

A library of novel bis-Schiff base derivatives based on thiobarbituric acid has been effectively synthesized by multi-step reactions as part of our ongoing pursuit of novel anti-diabetic agents. All these derivatives were subjected to in vitro α-glucosidase inhibitory potential testing after structural confirmation by modern spectroscopic techniques. Among them, compound 8 (IC50 = 0.10 ± 0.05 µM), and 9 (IC50 = 0.13 ± 0.03 µM) exhibited promising inhibitory activity better than the standard drug acarbose (IC50 = 0.27 ± 0.04 µM). Similarly, derivatives (5, 6, 7, 10 and 4) showed significant to good inhibitory activity in the range of IC50 values from 0.32 ± 0.03 to 0.52 ± 0.02 µM. These derivatives were docked with the target protein to elucidate their binding affinities and key interactions, providing additional insights into their inhibitory mechanisms. The chemical nature of these compounds were reveal by performing the density functional theory (DFT) calculation using hybrid B3LYP functional with 6-311++G(d,p) basis set. The presence of intramolecular H-bonding was explored by DFT-d3 and reduced density gradient (RGD) analysis. Furthermore, various reactivity parameters were explored by performing TD-DFT at CAM-B3LYP/6-311++G(d,p) method.

Discovery of biphenyls bearing thiobarbiturate fragment by structure-based strategy as Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors.

Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) is an important virulence factor that blocks the host immune response and facilitates M. tuberculosis growth in host cells. MptpB inhibitors are potential components of tuberculosis combination treatment. Herein, we present the development of new biphenyls MptpB inhibitors with greatly improved MptpB inhibition based on our reported thiobarbiturate lead 6 by rational design with the structure-based strategy. The eight biphenyls bearing thiobarbiturate fragment target compounds showed more potent MptpB inhibition (IC50: 1.18-14.13 µM) than the lead compound 6. Further molecular docking studies showed that compounds 13, 26, 27 and 28 had multiple interactions with active sites. Among them, compound 13 exhibited dose-dependent increased antituberculosis activity in mouse macrophages. The results displayed that the strategy of modification utilizing biphenyl scaffold was efficient. Our study identifies biphenyls bearing thiobarbiturate fragment as new MptpB inhibitors and verifies the therapeutic potential of antimycobacterial agent targeting MptpB.

Supramolecular polymerization of thiobarbituric acid naphthalene dye.

2-Thiobarbituric acid-functionalized naphthalene dye selectively self-assembles into crystalline fibers to show material properties that are different from those of a previously reported oxo-barbituric acid derivative affording curved supramolecular polymers via the formation of hydrogen-bonded rosettes. Detailed studies using 1H-NMR, DFT calculation and X-ray diffraction revealed that the crystalline fiber is formed through a tape-like hydrogen-bonding pattern due to the weaker hydrogen-bond-acceptor ability of the thiocarbonyl group.

The Effects of High-Pressure Processing on pH, Thiobarbituric Acid Value, Color and Texture Properties of Frozen and Unfrozen Beef Mince.

In this study, beef mince (approximately 4% fat longissmus costarum muscle of approximately 2-year-old Holstein cattle) was used as a material. High-pressure processing (HPP) was applied to frozen and unfrozen, vacuum-packed minced meat samples. The pH and thiobarbituric acid (TBA) values of the samples were examined during 45 days of storage. Color values (L*, a* and b*) and texture properties were examined during 30 days of storage. After freezing and HPP (350 MPa, 10 min, 10 °C), the pH value of minced meat increased (p > 0.05) and its TBA value decreased (p < 0.05). The increase in pH may be due to increased ionization during HPP. Some meat peptides, which are considered antioxidant compounds, increased the oxidative stability of meat, so a decrease in TBA may have been observed after freezing and HPP. While the color change in unpressurized samples was a maximum of 3.28 units during storage, in the pressurized sample, it exceeded the limit of 10 units on the first day of storage and exceeded the limit of 10 units on the third day of storage in the frozen and pressurized sample. Freezing and HPP caused the color of beef mince to be retained longer. The hardness, gumminess, chewability, adherence, elasticity, flexibility values of the pressurized and pressurized after freezing samples were higher than those of the unpressurized samples during storage. On the other hand, the opposite was the case for the adhesiveness values. In industrial applications, meat must be pressurized after being vacuum packed. If HPP is applied to frozen beef mince, some of its properties such as TBA, color, and texture can be preserved for a longer period of time without extreme change.

On 'The thiobarbituric acid reaction and the autoxidations of polyunsaturated fatty acid methyl esters' by Leland K.Dahle, Eldon G.Hill and Ralph T.Holman.

This commentary describes a highly cited paper by Dahle, Hill, and Holman, Arch Biochem Biophys. 1962; 98: 253-261. They showed that the oxidation products of polyunsaturated fatty acids reacted with thiobarbituric acid to give a colored product, which might be used to assess lipid oxidation.

Exogenously-Sourced Ethylene Positively Modulates Photosynthesis, Carbohydrate Metabolism, and Antioxidant Defense to Enhance Heat Tolerance in Rice.

The effect of exogenously-applied ethylene sourced from ethephon (2-chloroethyl phosphonic acid)was studied on photosynthesis, carbohydrate metabolism, and high-temperature stress tolerance in Taipei-309 and Rasi cultivars of rice (Oryza sativa L.). Heat stress increased the content of H2O2 and thiobarbituric acid reactive substances (TBARS)more in Rasi than Taipei-309. Further, a significant decline in sucrose, starch, and carbohydrate metabolism enzyme activity and photosynthesis was also observed in response to heat stress. The application of ethephon reduced H2O2 and TBARS content by enhancing the enzymatic antioxidant defense system and improved carbohydrate metabolism, photosynthesis, and growth more conspicuously in Taipei-309 under heat stress. The ethephon application enhanced photosynthesis by up-regulating the psbA and psbB genes of photosystem II in heat-stressed plants. Interestingly, foliar application of ethephoneffectively down-regulated high-temperature-stress-induced elevated ethylene biosynthesis gene expression. Overall, ethephon application optimized ethylene levels under high-temperature stress to regulate the antioxidant enzymatic system and carbohydrate metabolism, reducing the adverse effects on photosynthesis. These findings suggest that ethylene regulates photosynthesis via carbohydrate metabolism and the antioxidant system, thereby influencing high-temperature stress tolerance in rice.

Water-Soluble Products of Photooxidative Destruction of the Bisretinoid A2E Cause Proteins Modification in the Dark.

Aging of the retina is accompanied by a sharp increase in the content of lipofuscin granules and bisretinoid A2E in the cells of the retinal pigment epithelium (RPE) of the human eye. It is known that A2E can have a toxic effect on RPE cells. However, the specific mechanisms of the toxic effect of A2E are poorly understood. We investigated the effect of the products of photooxidative destruction of A2E on the modification of bovine serum albumin (BSA) and hemoglobin from bovine erythrocytes. A2E was irradiated with a blue light-emitting diode (LED) source (450 nm) or full visible light (400-700 nm) of a halogen lamp, and the resulting water-soluble products of photooxidative destruction were investigated for the content of carbonyl compounds by mass spectrometry and reaction with thiobarbituric acid. It has been shown that water-soluble products formed during A2E photooxidation and containing carbonyl compounds cause modification of serum albumin and hemoglobin, measured by an increase in fluorescence intensity at 440-455 nm. The antiglycation agent aminoguanidine inhibited the process of modification of proteins. It is assumed that water-soluble carbonyl products formed as a result of A2E photodestruction led to the formation of modified proteins, activation of the inflammation process, and, as a consequence, to the progression of various senile eye pathologies.

Comparing C2=O and C2=S Barbiturates: Different Hydrogen-Bonding Patterns of Thiobarbiturates in Solution and the Solid State.

Carbonyl-centered hydrogen bonds with various strength and geometries are often exploited in materials to embed dynamic and adaptive properties, with the use of thiocarbonyl groups as hydrogen-bonding acceptors remaining only scarcely investigated. We herein report a comparative study of C2=O and C2=S barbiturates in view of their differing hydrogen bonds, using the 5,5-disubstituted barbiturate B and the thiobarbiturate TB as model compounds. Owing to the different hydrogen-bonding strength and geometries of C2=O vs. C2=S, we postulate the formation of different hydrogen-bonding patterns in C2=S in comparison to the C2=O in conventional barbiturates. To study differences in their association in solution, we conducted concentration- and temperature-dependent NMR experiments to compare their association constants, Gibbs free energy of association ∆Gassn., and the coalescence behavior of the N-H‧‧‧S=C bonded assemblies. In Langmuir films, the introduction of C2=S suppressed 2D crystallization when comparing B and TB using Brewster angle microscopy, also revealing a significant deviation in morphology. When embedded into a hydrophobic polymer such as polyisobutylene, a largely different rheological behavior was observed for the barbiturate-bearing PB compared to the thiobarbiturate-bearing PTB polymers, indicative of a stronger hydrogen bonding in the thioanalogue PTB. We therefore prove that H-bonds, when affixed to a polymer, here the thiobarbiturate moieties in PTB, can reinforce the nonpolar PIB matrix even better, thus indicating the formation of stronger H-bonds among the thiobarbiturates in polymers in contrast to the effects observed in solution.

In vitro evaluation of the anticancer activity of barbituric/thiobarbituric acid-based chromene derivatives.

BACKGROUND: Cancer is one of the most important reasons for mortality worldwide. Several synthetic products have shown valuable efficiency as an anticancer medicines. Chromene derivatives have long been used as the promising compounds which are potent in inhibition of the growth of tumors. METHODS AND RESULTS: In this study, we investigate an anticancer activity of barbituric/thiobarbituric acid-based chromene derivates. For this purpose, viability, antioxidant and apoptotic assays were conducted using three different cancer cell lines (A2780, MCF7, and A549). In most cases, the antiproliferative activity of barbituric acid-based derivatives was higher than that of thiobarbituric acid-based compounds. Among 14 compounds, compound 4g was the most potent one, which showed the highest effect on cells by increasing the accumulation of ROS (up to 540% increase), increasing the level of caspase-3 and caspase-9 (~ 35% increase), and decreasing the mitochondrial membrane potential (2.5 folds reduction). To characterize the type of cell death involved into our experiment Annexin V/PI double staining of compound 4g was performed. The results showed that the number of late apoptotic and/or necrotic cells (Ann V + /PI +) increased fourfold upon treatment with IC50 concentration of 4g. CONCLUSIONS: Overall, the anti-proliferative activity of barbituric acid-based derivatives was higher than that of thiobarbituric acid compounds, and compound 4g can be introduced as a potential candidate to prevent various cancers.

Impact of the antioxidant quercetin on morphological integrity and follicular development in the in vitro culture of Bos indicus female ovarian fragments.

We evaluated the effect of quercetin on the in vitro culture of bovine ovarian fragments in relation to morphology, development, and oxidative stress. Ovaries (n = 12) from Nelore heifers (n = 6) were used. Each pair of ovaries was divided into nine fragments, and one fragment from each animal was fixed in Bouin solution for 24 h (histology control) or frozen (- 80°C; control for oxidative stress). Other ovarian fragments (n = 8) were distributed into concentrations of 0, 10, 25, and 50 µg/mL of quercetin added to the culture medium for 5 or 10 d. Data were analyzed by chi-square test or ANOVA followed by Tukey's test (P < 0.05). Treatment with 25 µg/mL quercetin resulted in the highest proportion of total intact follicles for 5 (67.3%) and 10 d (57.1%); the concentration of 25 µg/mL also presented the best proportion of developing follicles for 5 d (68.7%) and 10 d (62.8%). Treatment with 25 µg/mL quercetin resulted in significant ferric reduction for 10 d of culture, but not for 5 d. No difference (P > 0.1) was observed in the production of reactive oxygen species or in the oxidative degradation of lipids between treatments and non-cultivated controls. Treatment with 25 µg/mL quercetin preserved the morphological integrity of the developing follicles for 5 and 10 d of culture, in addition to promoting the best antioxidant potential after 10 d of culture in bovine ovarian fragments.

Chitosan-silica with hops ß-acids added films as prospective food packaging materials: Preparation, characterization, and properties.

In this study, silica (SiO2) and ß-acids were added to the chitosan films in order to improve the film's properties. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction analysis (XRD) were used to explore the structure of film. The results of mechanical test indicated that the film containing SiO2 (0.3%) and ß-acids (0.3%) could obtain a significant tensile strength (10.04 MPa). The complex films possessed a good inhibitory effect on three types of bacteria, and good antioxidant activity (>56%, DPPH). The release mechanism of ß-acids from the films exhibited Fickian diffusion (n < 0.45). During the storage of soybean oil, the films could well control the changes of the peroxide value, acid value and thiobarbituric acid reactant content. Overall, the biofilms not only possess good physical and chemical properties, but also prolongs the time of food storage.

Rise and decline of the barbiturate methitural for intravenous anesthesia: A systematic search and narrative synthesis.

BACKGROUND: Within the history of intravenous anesthesia, barbiturates represent a chapter of considerable importance. Although the reference barbiturate thiopental had several limitations, it dominated the scene of the intravenous anesthesia until the mid-1980s, when propofol was introduced on the market. In the meantime, several barbiturate derivatives were placed on the market and abounded. This work is aimed at evaluating the clinical impact of the barbiturate derivatives methitural, analyzing the reasons for its rapid abandonment, in the late 1950s. METHODS: A systematic methodology of the search was associated with a descriptive analysis of the bibliography found. A computer-operated search strategy using Medline and Google Scholar databases was implemented. The algorithm was composed by using the words "Diogenal" OR "Thiogenal" OR "Methitural" OR "Metigenal" OR "Neraval" including biochemical and marketed terms. A manual search of the sources was carried out, and precise inclusion and exclusion criteria were established. The narrative synthesis was conducted taken into account the historical context of anesthesia. RESULTS: The database search yielded 3645 records. Nineteen records were identified through other sources. After duplicates removing (n = 238), and exclusion of not pertinent 3027 records, 314 full-text articles were assessed for eligibility. Of those, other 225 papers were excluded and 89 articles were included in the qualitative synthesis. CONCLUSION: Although methitural could be useful in particular surgical settings such as short-acting surgery, and in patients with liver diseases, a limited advantage over thiopental, and its scarce market diffusion due to increased costs, have limited its use. Through a critical analysis of literature, the lack of high-quality studies does not allow us to draw definitive conclusions on the drug.

Topoisomerase IIα represses transcription by enforcing promoter-proximal pausing.

Accumulation of topological stress in the form of DNA supercoiling is inherent to the advance of RNA polymerase II (Pol II) and needs to be resolved by DNA topoisomerases to sustain productive transcriptional elongation. Topoisomerases are therefore considered positive facilitators of transcription. Here, we show that, in contrast to this general assumption, human topoisomerase IIα (TOP2A) activity at promoters represses transcription of immediate early genes such as c-FOS, maintaining them under basal repressed conditions. Thus, TOP2A inhibition creates a particular topological context that results in rapid release from promoter-proximal pausing and transcriptional upregulation, which mimics the typical bursting behavior of these genes in response to physiological stimulus. We therefore describe the control of promoter-proximal pausing by TOP2A as a layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription, possibly by regulating the accumulation of DNA supercoiling at promoter regions.

Photodynamic activity and photoantimicrobial chemotherapy studies of ferrocene-substituted 2-thiobarbituric acid.

A ferrocene-substituted thiobarbituric acid (FT) has been synthesized to explore its photophysical properties and photodynamic and photoantimicrobial chemotherapy activities. FT has an intense metal-to-ligand charge transfer (MLCT) band at ca. 575 nm. The ferrocene moiety of FT undergoes photooxidation to form a ferrocenium species which in turn produces hydroxyl radical in an aqueous environment, which was confirmed via the bleaching reaction of p-nitrosodimethylaniline (RNO). FT exhibits efficient PDT activity against MCF-7 cancer cells with an IC50 value of 5.6 µM upon irradiation with 595 nm for 30 min with a Thorlabs M595L3 LED (240 mW cm-2). Photodynamic inactivation of Staphylococcus aureus and Escherichia coli by FT shows significant activity with log reduction values of 6.62 and 6.16 respectively, under illumination for 60 min at 595 nm. These results demonstrate that ferrocene-substituted thiobarbituric acids merit further study for developing novel bioorganometallic PDT agents.

Biological Activity of a Thiobarbituric Acid Compound in Neuroblastomas.

BACKGROUND/AIM: We have previously reported the identification of the cytotoxic chemotype compound-I (CC-I) from a chemical library screening against glioblastoma. MATERIALS AND METHODS: The biological activity of CC-I on drug-resistant neuroblastomas [e.g., HFE gene variant C282Y stably transfected human neuroblastoma SH-SY5Y cells (C282Y HFE/SH-SY5Y), SK-N-AS] was characterized using cell culture models and in vivo mouse tumor models. RESULTS: CC-I had potent cytotoxicity on therapy-resistant neuroblastoma cells and limited cytotoxicity on human primary dermal fibroblast cells. In addition, CC-I showed a robust anti-tumor effect on therapy-resistant human neuroblastoma C282Y HFE/SH-SY5Y cells but not on SK-N-AS cells in a subcutaneous tumor model. CC-I induced phosphorylation of heat shock protein 27 (HSP27), protein kinase B (Akt), and c-Jun N-terminal kinase (JNK) in C282Y HFE/SH-SY5Y neuroblastoma cells. CONCLUSION: CC-I may be an effective therapeutic option for therapy-resistant neuroblastomas, especially if they express the C282Y HFE gene variant. Its anti-tumor effects are possibly through HSP27-Akt-JNK activation.

Bicyclic Basic Merbarone Analogues as Antiproliferative Agents.

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure-activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3-6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure-activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.

Synthesis and in vitro quantification of amyloid fibrils by barbituric and thiobarbituric acid-based chromene derivatives.

Neurodegenerative disease is caused by the abnormal build-up of proteins in and around cells called amyloid. The amyloid fibril formation and its mechanism have been investigated with various techniques, including dye-binding assay. Thioflavin T (ThT) has been one of the most widely used dyes for quantifying amyloid deposits, but ThT has a weak fluorescence signal especially at low concentration of amyloid fibrils, low lipophilicity and positive charge that makes it unable to cross the blood-brain barrier (BBB) to detect amyloid fibrils in vivo. Hence, there is a strong motivation for designing and developing the new compounds for in vitro amyloid quantification and in vivo amyloid imaging. The need for new probes to detect amyloid fibrils, especially within the cell, is highlighted by the fact that an accurate understanding of the molecular details of amyloid fibril formation is required to design and develop strategies for controlling the amyloid formation, and this needs more reliable probes for amyloid identification. In this work, we synthesized and applied barbituric and thiobarbituric acid-based chromene derivatives, as new fluorescent dyes to quantitatively detect the amyloid fibrils of bovine serum albumin (BSA) and human insulin in comparison with native soluble proteins or amorphous aggregation. Our results showed that among the 14 synthesized compounds, five compounds 4a, 4h, 4j, 4k, and 4l could selectively and specifically bind to amyloid fibrils while other compounds demonstrated a low-affinity binding. Furthermore, according to the cell viability experiment, compounds 4a, 4j and 4l at low concentration of compounds are not toxic, especially compound 4j which could be used as a suitable candidate for in vivo study. Further studies are needed to determine all the properties of compounds, especially in vivo experiments.

Photocytotoxicity of heavy-atom-free thiobarbituric acid functionalized pyrene derivatives against MCF-7 cancer cells.

Two thiobarbituric acid-functionalized pyrene derivatives (P1, P2) have been synthesized to explore the photophysical properties and photodynamic activity of dyes of this type. Both compounds exhibit an intense intramolecular charge transfer (ICT) band at ca. 470 nm, which is absent in the spectra of the precursor. P1 and P2 exhibit singlet oxygen generation on irradiation with light with moderate singlet oxygen yields of 0.36 and 0.32, respectively, in DMSO. P1 showed better photodynamic activity against MCF-7 cells with an IC50 value of 18.3 µM under illumination at 455 nm for 60 min with a Thorlabs M455L3 LED (330 mW.cm-2).

Day and blue light modify growth, cell physiology and indole-3-acetic acid production of Azospirillum brasilense Az39 under planktonic growth conditions.

AIM: In this work, we evaluated the effects of light on growth, cell physiology and stress response of Azospirillum brasilense Az39, a non-photosynthetic rhizobacteria, under planktonic growth conditions. METHODS AND RESULTS: Exponential cultures of Az39 were exposed to blue (BL), red (RL) and daylight (DL) or maintained in darkness for 24, 48 and 72 h. The biomass production and indole 3-acetic acid (IAA) biosynthesis increased by exposition to DL. Conversely, BL decreased IAA concentration through a direct effect on the molecule. The DL increased superoxide dismutase activity, hydrogen peroxide and thiobarbituric acid reactive substances levels, but the last one was also increased by BL. Both DL and BL increased cell aggregation but only BL increased biofilm formation. CONCLUSIONS: We demonstrated that both BL and DL are stress effectors for A. brasilense Az39 under planktonic growth conditions. The DL increased biomass production, IAA biosynthesis and bacterial response to stress, whereas BL induced cell aggregation and biofilms formation, but decreased the IAA concentration by photooxidation. SIGNIFICANCE AND IMPACT OF THE STUDY: Blue light and DL changes growth capacity, cell physiology and plant growth promotion ability of A. brasilense Az39 and these changes could be considered to improve the production and functionality of biofertilizers.