Thiobarbituric Acid Derivatives Research Articles

Substituent Position Dependent Photophysical Properties of Indole – Barbituric and Thiobarbituric Acid based Molecular Rotors

AbstractA series of 2‐ and 3‐methylindole (MI)‐based barbituric acid (BA) and thiobarbituric acid (TBA) derivatives (2MIBA, 2MITBA, 3MIBA and 3MITBA) in Donor (D)‐π‐Acceptor (A) configuration having strong intramolecular charge transfer (ICT) interactions were synthesized by the simple and efficient route. Methyl substituent at the 2‐ and 3‐ position alters the coplanarity of the DA systems leaving 2MI derivatives as nonplanar whilst 3MI derivatives as planar one and the latter forms an intramolecular hydrogen bond between indole N−H and −C=O of BA or TBA, which facilitates the excited state intramolecular proton transfer (ESIPT) emission in 3MIBA and 3MITBA. Comparing the UV‐visible absorption spectra in the solution phase reveals that the ICT band of 2MITBA and 3MITBA are red‐shifted from the 2MIBA and 3MIBA due to the stronger electron‐accepting nature of C=S than the C=O. Since these molecules exert photo‐induced intramolecular charge transfer followed by a rotation around the bridging methylene group, only weak fluorescence is noted. Nevertheless, in an aggregated state, both 3MIBA and 3MITBA exhibit significant aggregation‐induced enhanced emission (AIEE) characteristics in their THF/water mixture, but the effect is not promising for 2MIBA and 2MITBA. Further, melamine‐3MITBA co‐assembly aided through an intermolecular hydrogen bonding network can also be used as a solid‐state emitter.

Scope and Limitations of Barbituric and Thiobarbituric Amino Acid Derivatives as Protecting Groups for Solid‐Phase Peptide Synthesis: Towards a Green Protecting Group

AbstractDMB (Dimethylbarbituric) and DETB (Diethylthiobarbituric) are both barbituric and thiobarbituric acid derivatives respectively, that forms enamines with the Nα amine of amino acids. These compounds were found to be stable crystalline solids and show stability in the standard acidic and basic conditions used for solid‐phase peptide synthesis (SPPS) strategies. These protecting groups are cleaved by a mild solution of 2 % hydrazine hydrate in DMF and 2 % hydroxylamine in DMF, both at short reaction times. Their use in SPPS showed that DMB‐protected amino acids allow the preparation of peptides and therefore could be an alternative to the Fmoc strategy currently used. A further advantage of these protecting groups is that their preparation does not involve the concourse of phosgene derivatives and therefore they could be considered greener protecting groups than the carbamate‐based one.

Introduction of Agar-Entrapping as a Novel Strategy to Improve the Catalytic Activity of Moisture-Absorbing Acidic Ionic Liquids: A Case Study in the Synthesis of 5-Arylidene Barbituric Acids and Pyrano[2,3-d]Pyrimidinones

In this article, to improve the detrimental character of ionic liquids, called moisture absorbing, agar-trapping is introduced as an affordable and straightforward protocol. Using inexpensive biopolymer, agar, as a trapper is a brilliant advantage of the method led to an environmentally sustainable development. Moreover, to show the effect of this method, the catalytic ability of a prepared agar-trapped acidic ionic liquid and its free form was experimentally compared in the synthesis of barbituric and thiobarbituric acid derivatives. In the presence of the entrapped catalyst and under the optimized conditions the products were obtained in high yields during short reactions time.

Crystal Structure and Theoretical Investigation of Thiobarbituric Acid Derivatives as Nonlinear Optical (NLO) Materials

Here we report on the crystal structure of three enamine/imine TBA derivatives (1–3). Since the derivatives can take the form of enamine or imine tautomers, theoretical calculations were made to confirm that the former predominates due to higher stability (thermodynamic calculations). The enamines’ form was further corroborated by high activation energy (ΔG≠; which is >60 kcal/mol in all the cases), thus requiring a large amount of energy to pass the barrier (kinetics calculations). Furthermore, 1–3 were found to show high static hyperpolarizability (βtot), thereby making them potential candidates as nonlinear materials for electro-optical devices and crystal engineering.

Synthesis of Some New Barbituric and Thiobarbituric Acids Bearing 1,2,4-Triazine Moiety and Their Related Systems as Herbicidal Agents

In search for highly bioactive barbituric and thiobarbituric acid derivatives, some new barbituric and thiobarbituric acids bearing 1,2,4-triazine moiety and their related systems (5–13) have been obtained from the addition of isocyanate and isothiocyanate to 3-amino-5,6-diphenyl-1,2,4-triazine (1) followed by ring closure reactions with diethyl malonate. Also, chemical reactivities of the related systems were obtained from the condensation of barbituric and thiobarbituric acid derivatives with aromatic aldehyde and/or fluoroacylation reactions. The structure of all the products was deduced from both elemental analysis and spectral data (IR, 1H NMR, 13C NMR, and MS). The herbicidal activity was also evaluated for the products.

Ameliorative potential of sitagliptin and/or calcipotriol on lipopolysaccharide-induced Alzheimer's disease

Background: Alzheimer's disease (AD) is a progressive neuropsychiatric disorder that causes dementia. It mostly affects people older than 65 years. The exact mechanisms of AD are not fully understood but affection of apoptosis, oxidative stress and neuroinflammation may be contributing factors. Aim: To evaluate the ability of sitagliptin and/or calcipotriol to attenuate lipopolysaccharide (LPS)-induced AD in mice and to elucidate their possible mechanisms of action. Methods: Sixty male Balb/c mice were divided into 6 equal groups: Control; LPS; LPS + carboxymethyl cellulose; LPS + Sitagliptin; LPS + Calcipotriol; and LPS + Sitagliptin + Calcipotriol group. Behavioral tests, tissue catalase (CAT), superoxide dismutse (SOD) and thiobarbituric acid derivatives (TBARS) were assessed. Also, tissue transforming growth factor beta-1 (TGF-β1), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were determined. Parts of the hippocampus were subjected to histopathological, immunohistochemical and electron microscopic examination. Results: Administration of sitagliptin and/or calcipotriol prior to LPS injection induced significant increase in the recognition index, tissue CAT and SOD associated with significant decrease in tissue TBARS, TNF-α, IL-6 and TGF-β1 and significant improvement of the histopathological, immunohistochemical and electron microscopic picture compared to LPS group. These changes were significant in sitagliptin/calcipotriol combination group compared to the use of each of these drugs alone. Conclusion: Sitagliptin/calcipotriol combination might represent a new therapeutic modality for amelioration of Alzheimer’s disease.

Corrective infl uence of dihydroquercetin on oxidative metabolism state in drivers of Northern region

Professional drivers during their work are constantly subjected to toxic influence of chemical elements in automobile exhaust gases that cause excessive accumulation of lipid peroxidation products. The study covered 182 male inhabitants (aged 32,6±6,2 years) of Hanty-Mansiysk autonomous district: 94 drivers and 88 clerks. The drivers, when compared to the clerks, demonstrated reliably higher values of lipid peroxidation: lipids hydroperoxide (p = 0.026), active derivatives of thiobarbituric acid (p = 0.003), coefficient of oxidative stress (p = 0.002) with lower parameters of antioxidant system: general antioxidant activity (p<0.001), thiolic state (p = 0.002). After 3 months of correction by means of natural antioxidant dihydroquercetin (75 mg daily), the drivers demonstrated not only statistically significant decrease of lipid peroxidation parameters: lipids hydroperoxide, coefficient of oxidative stress (p = 0.007) and increased values of antioxidant system: general antioxidant activity (p = 0.003), thiolic state (p = 0.05), but also considerable improvement of general state and performance.

New thiobarbituric acid scaffold-based small molecules: Synthesis, cytotoxicity, 2D-QSAR, pharmacophore modelling and in-silico ADME screening

A series of twenty five new thiobarbituric acid derivatives, viz. 3a-h, 4–7, 8a-c, 9, 10a-c, 11 and 12a-d, were designed and synthesized as potential cytotoxic agents. In-vitro screening of the new compounds against the three human cancer cell lines Caco-2, HepG-2 and MCF-7 was performed to assess their intrinsic activity. Compound 12d exhibited potent sub-micromolar activity against HepG-2 and MCF-7 (IC50 = 0.07 and 0.08 μM, respectively). In-silico pharmacophore modelling of this chemotype compounds disclosed a five features' pharmacophore model representing essential steric and electronic fingerprints essential for activity. Finally, a 2D-QSAR model was devised to quantitatively correlate the 2D molecular feature descriptors of this series of thiobarbiturates with their cytotoxic activity against MCF-7. Finally, in silico evaluation of the physicochemical and ADME properties of these derivatives was performed.

When Serendipity Knocks on the Door: Synthesis and Physicochemical Characterization of 7-Chloro-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one

Herein, we present the serendipitous obtaining of 7-chloro-2,3-dihydro-5H-thiazolo [3,2-a]pyrimidin-5-one in 40% yield by using POCl3 and a thiobarbituric acid derivative. The thiazolopyrimidine derivative was characterized by 1H nuclear magnetic resonance (NMR), UV-Vis, and Fourier transform infrared (FTIR) spectroscopy. Additionally, the structure was confirmed by single crystal X-ray diffraction, where it was found that the compound crystallizes in the P-1 triclinic space group with two conformeric molecules of 7-chloro-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-5-one by asymmetric unit. Also, from the structural data was studied the supramolecular interactions using Hirshfeld surface analysis and 2D fingerprint plots.

Synthesis of Some New Aryl Thiobarbituric Acid Derivatives as Antibacterial and Antifungal Agents

Synthesis of Some New Aryl Thiobarbituric Acid Derivatives as Antibacterial and Antifungal Agents

Crystal structure, spectroscopic studies and theoretical studies of thiobarbituric acid derivatives: understanding the hydrogen-bonding patterns.

In addition to their wide-ranging applications in the pharmaceutical industry, thiobarbituric acid (TBA) derivatives are also known to possess applications in engineering and materials science. 20 TBA derivatives, with diversity at the N and C-5 positions through acylation, Schiff base formation, Knoevenagel condensation, thioamide and enamine formation, were studied. The absolute configurations for six derivatives, namely 5-acetyl-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C10H14N2O3S, A01, 1,3-diethyl-5-propionyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C11H16N2O3S, A02, tert-butyl [1-(1,3-diethyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate, C18H29N3O5S, A06, 1,3-diethyl-4,6-dioxo-2-thioxo-N-(p-tolyl)hexahydropyrimidine-5-carbothioamide, C16H19N3O2S2, A13, 5-(1-aminoethylidene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C10H15N3O2S, A17, and 5-(1-aminopropylidene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C11H17N3O2S, A18, were confirmed by single-crystal X-ray crystallography, which indicates the formation of intramolecular hydrogen bonding in all six cases and intermolecular hydrogen bonding for A17. In A13, the presence of two intramolecular hydrogen bonds was observed. The stabilization of the enol form over the keto form was confirmed by computation. In order to convert the keto form to the enol form, an energy barrier of 55.05 kcal mol-1 needs to be overcome, as confirmed by transition-state calculations.

Microwave Irradiation Assists the Synthesis of a Novel Series of bis-Arm s-Triazine Oxy-Schiff Base and Oxybenzylidene Barbiturate Derivatives.

A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde was prepared and fully characterized. The reaction was carried out via stepwise nucleophilic aromatic substitution of chlorine atoms in cyanuric chloride. The first chlorine was substituted by different amines (morpholine, piperidine, or diethylamine) to afford 2,4-dichloro-6-substituted-1,3,5-triazine. The second and third chlorines were substituted by benzaldehyde derivatives in the presence of Na2CO3 as a HCl scavenger to afford the target products: s-triazine oxyaldehyde derivatives (dipodal). The dipodal derivatives were reacted with acid hydrazide, hydralazine, barbituric, or thiobarbituric acid derivatives using conventional heating or microwave irradiation to afford the di-arm s-triazine oxy-Schiff base and oxybenzylidene barbiturate derivatives in good yields. Microwave irradiation done in less solvent afforded the target product in less reaction time with good yield and purity. These types of derivatives might have special interest in coordination and medicinal chemistry.

Age-related features of activity of free radical oxidation in erythrocyte membranes and blood plasma in postinfarction cardiosclerosis in rats

Aim. To determine the presence of lipid and protein peroxidation products in erythrocyte membranes and blood plasma in rats of different ages in an intact state and with developed postinfarction cardiosclerosis.
 Methods. In rats aged 4, 12, 24 months postinfarction cardiosclerosis was modeled by coronary occlusion. In blood plasma and erythrocyte membranes, products reacting with thiobarbituric acid and carbonyl derivatives of protein amino acid residues were determined.
 Results. In erythrocyte membranes of intact animals aged 12 months, a decrease of the content of thiobarbituric acid-reacting products was revealed in comparison with 4 month-old animals, and in 24 months-old animals the index significantly exceeded the values of young subjects. In the blood plasma of intact animals aged 12 and 24 months, an increased content of thiobarbituric acid-reacting products with respect to rats aged 4 months was revealed. In postinfarction cardiosclerosis, an increase in the accumulation of thiobarbituric acid-reacting products was observed in erythrocyte membranes of 4 and 24 months-old animals. In blood plasma, an increase of this parameter was noted only in the group of 4 months-old animals with postinfarction cardiosclerosis. In erythrocyte membranes of intact rats of all age groups, no differences in the level of carbonyl derivatives of protein amino acid residues were observed, and in blood plasma it significantly increased with age. In 4 and 12 months-old animals with postinfarction cardiosclerosis, significant increase of carbonyl derivatives of protein amino acid residues was mostly pronounced in erythrocyte membranes. In 24 months-old animals with postinfarction cardiosclerosis, this parameter in the membranes and blood plasma was stable.
 Conclusion. The intensity of processes of cell membrane and blood lipid peroxidation has pronounced age-dependent features that persist in postinfarction cardiosclerosis; proteins of erythrocyte membranes of intact animals are subject to peroxide modification to a lesser degree than blood plasma proteins; in postinfarction cardiosclerosis formation in 4 and 12 months-old animals, carbonyl derivatives of protein amino acid residues are more intensively accumulated in erythrocyte membranes compared to blood plasma.

Efficient procedure with new fused pyrimidinone derivatives, Schiff base ligand and its La and Gd complexes by green chemistry

Synthetic strategies were developed for the construction of some newer more potent derivatives of thiobarbituric acid and its Schiff base metal complexes in both bulk and at the nanoscale.

Taurine as a green bio-organic catalyst for the preparation of bio-active barbituric and thiobarbituric acid derivatives in water media

Taurine, a β-amino acid that is abundantly available in the tissues of human and animals, is efficiently used as a green bio-organic catalyst in the preparation of some of the biologically active barbituric and thiobarbituric acid derivatives. In the presence of taurine, 5-Arylidene (thio) barbituric acid derivatives were prepared via Knovenagel reaction between aldehydes and (thio)barbituric acid. Using this reagent also pyrano[2,3-d]pyrimidinone(thione) derivatives were synthesized through a three-component reaction between aldehydes, (thio)barbituric and malononitrile. Both reactions are performed in water with good to excellent yields during acceptable reaction times. No organic solvent was used during reaction or separation steps and no extra-purification was exerted. Meanwhile, reusability of taurine was easy and noticeably high.

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

Barbituric and thiobarbituric acid derivatives have become progressively attractive to medicinal chemists due to their wide range of biological activities. Herein, different series of 1,3,5-trisubstituted barbiturates and thiobarbiturates were prepared in moderate to excellent yields and their activity as xanthine oxidase inhibitors, antioxidants, antibacterial agents and as anti-proliferative compounds was evaluated in vitro. Interesting bioactive barbiturates were found namely, 1,3-dimethyl-5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6c) and 1,3-dimethyl-5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6e), which showed concomitant xanthine oxidase inhibitory effect (IC50 values of 24.3 and 27.9 μM, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC50 values of 18.8 and 23.8 μM, respectively). In addition, 5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6d) also revealed DPPH radical scavenger effect, with an IC50 value of 20.4 μM. Moreover, relevant cytotoxicity against MCF-7 cells (IC50 = 13.3 μM) was observed with 5-[[(2-chloro-4-nitrophenyl)amino]methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (7d). Finally, different 5-hydrazinylethylidenepyrimidines revealed antibacterial activity against Acinetobacter baumannii (MIC values between 12.5 and 25.0 μM) which paves the way for developing new treatments for infections caused by this Gram-negative coccobacillus bacterium, known to be an opportunistic pathogen in humans with high relevance in multidrug-resistant nosocomial infections. The most promising bioactive barbiturates were studied in silico with emphasis on compliance with the Lipinski's rule of five as well as several pharmacokinetics and toxicity parameters.

Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells

A series of novel thio- and seleno-barbituric acid derivatives were synthesized by varying the substituents at N1 and N3 (ethyl, methyl, allyl, and phenyl), and C5 tethered with dienyl and trienyl moieties attached to substituents such as phenyl, 2-furanyl, 2-thiophenyl, 1-naphthyl, and 3-pyridyl. The cytotoxic potential of these derivatives was evaluated by using MTT assay against melanoma cell lines expressing either wild-type (CHL-1) or mutant (UACC 903) BRAF gene. Among all, 2b and 8b were identified as the most potent compounds. Both 2b and 8b inhibited viability of various melanoma cells and induced cell death as evidenced by Live and Dead assay. Western blot analysis showed that they induce PARP cleavage and inhibit anti-apoptotic Bcl-2, Bcl-xL and Survivin in a dose-dependent manner within 24 h of the treatment. Novel thiobarbituric acid analogs also inhibited viability of various other solid tumor cell lines, such as pancreatic, breast, and colon. Overall, 2b, 2d, and 8b emerged as the most effective compounds and make good leads for the development of future therapeutic agents.

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC50=840±1.73µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC50=19.46±1.84–415.8±4.0µM). Compound3i(IC50=19.4±1.84µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.

Biological activity of 5-benzylidene thiobarbituric acid derivative against some bacteria isolated from burns infections

A total of fifty (50) samples were collected from burn infections from AL-Sader Medical City in Alnajaf Alashraf during the period from the 24th of January to the 4th of April . Different percentages of different bacteria were noted as follows , Pseudomonas aeruginosa was the highest percentage about 33% followed by Ps. florescence 8( 16 %) , both E.coli & Klebsiella Sp comprised 6 (12%) ,and Aeromonas sp was the lowest ratio comprising 2% . The most bacteria appeared resistance to antibiotics, Pseudomonas aeruginosa was found to be resistant to most of the therapeutic agents. In this paper a synthesis of 5-benzylidene thiobarbituric acid derivative have been described. The route of preparation involved the uses of thiobarbituric acid as starting material and treated with 4-dimethylaminobenzaldehyde compound to give required derivative this compound have been identified by a spectroscopic method like H-NMR, IR and CHNS analysis and also by measuring its melting point.A simple synthetic route for 5-(4- dimethylaminobenzylidene)thiobarbituric acid by the condensation reaction of 4-dimethylaminobenzaldehyde with thiobarbituric acid in water without catalyst is described. The results revealed that proteus sp. was affected by chemical model more than the other bacteria , increasing the concentration of the compound increases the inhibition zone .also bacteria Klebseilla sp. Pseudomonas aeruginosa. affected by compound model ,but bacteria Staphylococcus arueus was not affected by any concentration of compound. The aim of of this study was to determine the model of chemical compounds effect on the growth of some bacteria isolated from buruns in vitro.

ChemInform Abstract: DABCO‐Based Ionic Liquids: Green and Recyclable Catalysts for the Synthesis of Barbituric and Thiobarbituric Acid Derivatives in Aqueous Media.

AbstractArylidine barbituric and thiobarbituric acids are prepared by reaction of barbituric acid and its thio‐analogue with various aldehydes under green reaction conditions.