Barbituric Acid Derivatives Research Articles

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.

Buthalital and methitural - 5,5-substituted derivatives of 2-thio-barbituric acid forming the same type of hydrogen-bonded chain.

The mol-ecule of buthalital, (I) [systematic name: 5-(2-methyl-prop-yl)-5-(prop-2-en-1-yl)-2-sulfanyl-idene-1,3-diazinane-4,6-dione], C11H16N2O2S, exhibits a planar pyrimidine ring, whereas the pyrimidine ring of methitural, (II) [systematic name: 5-(1-methyl-but-yl)-5-[2-(methyl-sulfan-yl)eth-yl]-2-sulfanyl-idene-1,3-diazinane-4,6-dione], C12H20N2O2S2, is slightly puckered. (I) and (II) contain the same hydrogen-bonded chain structure in which each mol-ecule is connected, via four N-H⋯O=C hydrogen bonds, to two other mol-ecules, resulting in a hydrogen-bonded chain displaying a sequence of R22(8) rings. The same type of N-H⋯O=C hydrogen-bonded chain has previously been found in several 5,5-disubstituted derivatives of barbituric acid which are chemically closely related to (I) and (II).

Nanoporous Na+-montmorillonite perchloric acid as an efficient heterogeneous catalyst for synthesis of merocyanine dyes based on isoxazolone and barbituric acid

Nanoporous Na+-montmorillonite perchloric acid (MPA) as a novel heterogeneous solid acid catalyst was easily prepared. The physico-chemical properties of the catalyst were analyzed by a variety of techniques including X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), energy dispersive X-ray spectroscopy (EDX), Brunauer-Emmett-Teller (BET) and nitrogen adsorption-desorption measurements, pH analysis and Hammett acidity function. The prepared reagent showed excellent catalytic activity for the green one-pot, three component synthesis of 3-methyl-4-arylmethylene-isoxazol-5(4H)-one, pyrano [2,3-d] pyrimidinone and 5-arylidine barbituric acid derivatives in aqueous media. The remarkable features of the present protocol are availability and low cost of the starting materials, reusability of the catalyst, short reaction times and high yields of the products.

Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids.

The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5-disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C-C bond forming reactions with vinyl ketones or Morita-Baylis-Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.

3d/4f Coordination Clusters as Cooperative Catalysts for Highly Diastereoselective Michael Addition Reactions.

Michael addition (MA) is one of the most well studied chemical transformation in synthetic chemistry. Here, we report the synthesis and crystal structures of a library of 3d/4f coordination clusters (CCs) formulated as [ZnII2YIII2L4(solv)X(Z)Y] and study their catalytic properties toward the MA of nitrostyrenes with barbituric acid derivatives. Each CC presents two borderline hard/soft Lewis acidic ZnII centers and two hard Lewis acidic YIII centers in a defect dicubane topology that brings the two different metals into a proximity of ∼3.3 Å. Density functional theory computational studies suggest that these tetrametallic CCs dissociate in solution to give two catalytically active dimers, each containing one 3d and one 4f metal that act cooperatively. The mechanism of catalysis has been corroborated via NMR, electron paramagnetic resonance, and UV-vis. The present work demonstrates for the first time the successful use of 3d/4f CCs as efficient and high diastereoselective catalysts in MA reactions.

Improvements in self-curing composites

PurposeThe purpose of this study was to test the influence of a barbituric acid derivative acting as a catalyst and small amounts of pyrolytic silica in acrylic resins on color stability, solubility and sorption of a composite. Materials and methodsA series of two-component powder/liquid resin systems were prepared. Monomer-like mixtures (bis-GMA, TEGDMA, tertiary amine 60/40) and a quartz powder with additions of various silica and barbituric acid derivatives were used. Temperature of the material during polymerization was measured with the use of a thermometer. In addition, the material’s flexural and compressive strength, sorption and solubility were tested pursuant to ISO4049:2009. ResultsThe powder-based acrylic composition in a liquid mixed immediately before use, after an addition of a 0.5% barbituric acid derivative, has a lower temperature during the polymerization process (a reduction from 43°C to 37°C), whereas color stability over time is improved, with ΔE=1.81 for samples of powder mixtures containing between 0.45% of BPO and 0.15% of barbituric acid derivatives. For silanized quartz powder with 0.55% BPO and 0.1% BA+0.5% Aerosil R711, the obtained sorption value was 4.57±0.22μg/mm3, whereas solubility was 1.60±0.32μg/mm3. ConclusionsNew catalytic system with barbituric acid derivative, improves color stability for samples stored at room condition and under light of high intensity. A two-phase composite (bis GMA TEGDMA/Quartz), with a new catalytic system with barbituric acid derivatives, has a lower self-cured temperature. Adding a small quantity of hydrophobic silica (0.5%) has a significant influence, with reduced sorption and solubility of the material.

ABC Supramolecular Triblock Copolymer by ROMP and ATRP

We report the controlled polymerization of three heterotelechelic polymers from supramolecular motif-bearing initiators, their assembly into supramolecular A/B/C triblock copolymers, the morphology of the resulting block copolymers, and their disassembly. The individual blocks are synthesized in a controlled or living fashion via ring-opening metathesis polymerization (ROMP) of norbornenes (block B) or atom-transfer radical polymerization (ATRP) of styrenes (block A) and methacrylates (block C). The building blocks are assembled via metal-coordination between blocks A and B using a palladated SCS pincer complex and pyridine, and hydrogen bonding between blocks B and C using Hamilton Wedge and barbituric acid derivatives. Scanning-transmission electron microscopy and small-angle X-ray scattering reveal lamellar domains of approximately 23, 15, and 21 nm for bulk samples of the A/B and B/C diblock copolymers and A/B/C triblock copolymers, with 1:1 and 1:1:1 block feed ratios, respectively. Nanoscale feature...

A Novel Small Molecule Inhibitor of Human DNA Polymerase Eta Modulates the Efficacy of Cisplatin in Cancer Cells

Chemotherapeutic strategies involving platinum‐based drugs rely on DNA damage to limit tumor growth. Activation of DNA damage response pathways can modulate patient response to these types of therapies. For example, translesion DNA synthesis (TLS) by human DNA polymerase (pol) eta (η) can render platinum‐based chemotherapy ineffective through the direct bypass of DNA damage. Therefore, targeting hpol η with small‐molecule inhibitors is a promising strategy for combating chemoresistance in certain types of cancer, such as ovarian cancer, that rely on hpol η to survive genotoxic chemotherapy. The main objective of our study was to identify small molecule inhibitors of hpol η that modulate the efficacy of genotoxic anti‐cancer drugs in an effort to improve patient outcomes. Towards that end, the catalytic activity of hpol η was measured in the presence of eighty‐five novel indole thio‐barbituric acid (ITBA) and indole barbituric acid (IBA) derivatives. Several compounds that inhibit hpol η activity with low micromolar IC50s were identified from this initial screen. One of these compounds, PNR‐7‐02, an ITBA derivative with both N‐napthoyl moiety and 5‐chloro substituent on the indole ring inhibited hpol η activity with an IC50 value of 8 μM. PNR‐7‐02 also inhibited hRev1 and hpol lambda (λ) with low micromolar IC50, but inhibition by PNR‐7‐02 was approximately ten‐fold more potent against hpol η than B‐family pols. Michaelis‐Menten kinetic analysis revealed a partial competitive mechanism of inhibition of hpol η activity. Chemical labeling and molecular docking results further supported the kinetic mechanism of inhibition. A target‐dependent effect on cell viability was observed when comparing hpol η‐proficient and hpol η‐deficient HAP‐1 cells co‐treated with cisplatin and PNR‐7‐02. The calculated combination index values indicated a strong synergy between cisplatin and PNR‐7‐02 in hpol η‐proficient cells. This synergy was not evident in the hpol η knockout cells, supporting the idea that PNR‐7‐02 modulates cisplatin toxicity in a hpol η‐dependent manner. Results from cell sorting experiments were consistent with synergy observed between cisplatin and PNR‐7‐02. In summary, our lab has performed the first quantitative structure activity relationship for TLS pols to identify potent inhibitor of hpol η that sensitizes cancer cells to cisplatin treatment.Support or Funding InformationThis work was supported by NIH grants GM 084460 and CA 183895 (to R.L.E.).

The Kinetics and Mechanism of the Reaction between Barbituric Acid and Glycidol, Part II: Glycidol Reacts with Imide and Methylene Groups

ABSTRACTTwo derivatives of barbituric acid, 5,5‐diethylbarbituric acid and 1,3‐dimethyl‐barbituric acid, were used to react with glycidol. The kinetics of reactions was studied by continuous determination of epoxide number and acidic number in the reaction mixture aliquots. Based upon the kinetic experiments, the rate equation was formulated, which was consistent with product spectral identification of the derivatives as well as with previously studied reaction of barbituric acid with glycidol. Reaction mechanisms of glycidol with methylene and imide groups of barbituric acid have been proposed.

The Kinetics and Mechanism of the Reaction between Barbituric Acid and Glycidol, Part I: The Products Analysis

ABSTRACTThe hydroxyalkyl derivatives of barbituric acid (BA) were formed in the reaction between BA and glycidol (GL). The reaction was performed at BA:GL 1:1, 1:2, and 1:4 molar ratios in DMF or without solvent. The progress of reaction was monitored by determination of the epoxide number and IR and NMR spectroscopy. It was found that primary reactive site of BA was C5 and further nitrogen ring atoms. BA was always involved in keto‐enol equilibrium, the latter form being less reactive. The isolated hydroxyalkyl derivatives are useful precursors of oligoetherols with the pyrimidine ring.

3B03 ジベンゾフェナジン誘導体及びバルビツール酸誘導体Ni錯体におけるカラムナー相の過渡光電流測定法による正孔移動特性評価(分子配向エレクトロニクス,口頭発表,2015年日本液晶学会討論会)

3B03 ジベンゾフェナジン誘導体及びバルビツール酸誘導体Ni錯体におけるカラムナー相の過渡光電流測定法による正孔移動特性評価(分子配向エレクトロニクス,口頭発表,2015年日本液晶学会討論会)

Enantioselective organocatalytic Michael additions of N,N'-dialkylbarbituric acids to enones.

N,N'-Dialkylbarbituric acids as cyclic malonamide donors were successfully used in the enantioselective Michael addition reaction of enones. Using cinchona alkaloid-based bifunctional squaramide as an organocatalyst, this Michael reaction of N,N'-di-tert-butylbarbituric acid with various enones features a highly enantioselective (91-99% ee) production of the corresponding optically active 5-substituted barbituric acid derivatives. The transformations of the Michael product for the barbituric acid structural unit were realized in two ways, deprotection to remove the N-tert-butyl group and alkylation to produce 5,5-disubstituted barbituric acid derivatives.

Synthesis and spectral-luminescent properties of 5-substituted polyaryl derivatives of barbituric acid

New substituted barbituric acid derivatives containing a 4,5,6,7-tetrahydroindole moiety have been synthesized by three-component condensation. Luminescence of crystals and solutions of the compounds synthesized have been studied; a maximum luminescence intensity and a minimum Stokes shift have been found in the 1-naphthyl derivative.

The development of the method for enzymatic hydrolysis for the extraction of toxic substances from the hair samples

The objective of the present study was to develop and validate the method for the extraction of toxic substances from the hair samples as exemplified by enzymatic hydrolysis of barbituric acid derivatives. The experiments were carried out with the use of laboratory animals (white female rats and albino guinea pigs) that had been daily given a phenobarbital solution per os during 4 months preceding the study. The hairs obtained from the experimental animals were subjected to acid hydrolysis with a 6 mole hydrochloric acid and enzymatic hydrolysis with the use of chymopsin, trypsin, chymotrypsin, and papain solutions. The analysis of the extracted materials was performed by means of gas chromatography with mass-selective detection. The application of the proposed method for enzymatic hydrolysis produced the better results than acid hydrolysis. This technique was validated. The results of the study made possible the comparative characteristic of the effectiveness of acid and enzymatic hydrolysis.

The identification of barbituric acid derivatives in the old blood stains on textiles

Thus article was designed to report a few cases of the identification of barbituric acid derivatives in the old blood stains on the clothes and other textiles. The data presented give evidence that barbiturates are capable of persisting in dry blood stains during rather a long period. The authors emphasize the necessity of mandatory control investigations to avoid obtaining the false positive results.

Molecular structure and spectroscopic investigations combined with hypoglycemic/anticancer and docking studies of a new barbituric acid derivative

The one-pot synthesis reaction of barbituric acid derivative, 1,3-cyclohexandione, and 4-fluorobenzaldehyde in water mediated by NHEt2 as base afforded 4 with excellent yield. The synthesized compound was characterized by spectrophotometric tools as well as X-ray single crystal diffraction technique. The stability of the nine possible isomers of the synthesized compound was studied using the B3LYP method and 6-31G(d,p) basis set. The electronic and spectroscopic properties of the most stable isomer were predicted. The UV–Vis absorption spectrum displayed two bands at 203 and 257 nm in the solvent chloroform. The latter was calculated at 235.6 nm (f = 0.1995) in the gas phase due to H-2→L (42%) and H-1→L+2 (14%) excitations. In solution, using chloroform as a solvent, a slight bathochromic shift to 237.6 nm with an increase in the absorption intensity (f = 0.2898) was predicted. The molecular orbital energy level diagram of this transition band was characterized mainly by π-π* transitions. The 13C and 1H NMR chemical shifts correlated well with the experimental data. The correlations had higher correlation coefficients (R2) when solvent effects were considered. The atomic charges were calculated using natural population analysis and the charged regions were presented using a molecular electrostatic potential (MEP) map. The synthesized compound was examined as a hypoglycemic agent via inhibition of α-glucosidase and β-glucuronidase enzymes. Its inhibitory activity against α-glucosidase was 10 times greater than the inhibitory activity of the standard drug acarbose (IC50 77.9 ± 0.3 μM and 840 ± 1.73 μM, respectively). Moreover, the target compound was evaluated for anticancer activity against MCF-7, H460, 3T3, and Hela cell lines. It demonstrated inhibitory activity against the MCF-7 and H460 cell lines with IC50 5.80 ± 0.12 and 19.6 ± 0.5 μM, respectively, in comparison to doxorubicin. The docking study was performed using the OpenEye program.

A new approach to understanding structure, functions and classificasion of GABA-benzodiazepine receptor complex, a molecular target for creation of new anticonvulsants on the base of inhibitory amino acids

The GABA molecule was shown to the methods of quantum mechanic characteristics and molecular geometry has three conformational states: linear (GABA-1 conformer), cyclic (GABA-2 comformer) and bucket-like (GABA-3 conformer). The play different functions in the brain neurons: cyclic and bucket-like conformers play role of endogenous transmitters, and linear conformer participates in neuronal metabolism. The theoretical conformational analysis shows there are two types of GABA receptors in the CNS neurons: GABA-2 receptors, agonists of which are cyclic conformer of GABA, glycine and β-alanine and antagonists are bemegride, pentilentetrazol and strychnine; and GABA-3 receptors, agonists of which is bucket-like conformer of GABA and antagonists are picrotoxin and bicuculline. Anticonvulsive and other behavioral effects of derivatives of barbituric acid, benzazepine, benzodiazepine, gidantoine, succinimide and oxasolidindione are realized probably via GABA-2 receptors to switch on them the following functional centers of their structure are nessesary: α, γ and [δ-ε] for barbitirates; β, [δ-ε] and γ for carbamazepine; β and [δ-ε] for benzodiazepine derivatives, gabapentine and vigabatrine; α, β, γ and [δ-ε] for gidantoine and oxasolidindione derivatives; α, β, γ for succinimide derivatives. The power of any behavioral effect of anticonvulsants and inhibitory amino acids depends on power, location and numbers of hydrogen bounds developed between active centers of pharmacophore of anticonvulsant or inhibitory amino acids and active centers of functional skeleton of GABA-2 receptor complex, these properties determine absense of nootropic activity in anticonvulsive drugs and presense of them in inhibitory amino acids. It is concluded there are perspectives of synthesis of conpounds, pharmacophore of which should be like as cyclic conformer of GABA, glycine and β-alanine on their quantum mechanic characteristics and molecular geometry

Supramolecular chiral host–guest nanoarchitecture induced by the selective assembly of barbituric acid derivative enantiomers

Barbituric acid derivatives are prochiral molecules, i.e. they are chiral upon adsorption on surfaces. Scanning tunneling microscopy reveals that barbituric acid derivatives self-assemble into a chiral guest–host supramolecular architecture at the solid–liquid interface on graphite. The host nanoarchitecture has a sophisticated wavy shape pattern and paired guest molecules are nested insides the cavities of the host structure. Each unit cell of the host structure is composed of both enantiomers with a ratio of 1:1. Furthermore, the wavy patterns of the nanoarchitecture are formed from alternative appearance of left- and right-handed chiral building blocks, which makes the network heterochiral. The functional guest–host nanoarchitecture is the result of two-dimensional chiral amplification from single enantiomers to organizational heterochiral supramolecular self-assembly.

Molecular Structure, Spectroscopic and DFT Computational Studies of Arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Reaction of barbituric acid derivatives and di-substituted benzaldehyde in water afforded arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives (1 and 2). The one step reaction proceeded efficiently, smoothly, and in excellent yield. The arylidene compounds were characterized by spectrophotometric tools plus X-ray single crystal diffraction technique. Quantum chemical calculations were performed using the DFT/B3LYP method to optimize the structure of the two isomers (1 and 2) in the gas phase. The optimized structures were found to agree well with the experimental X-ray structure data. The highest occupied (HOMO) and lowest unoccupied (LUMO) frontier molecular orbitals analyses were performed and the atomic charges were calculated using natural populationanalysis.

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.