Thiobarbituric Acid Derivatives Research Articles

Synthesis and Antimicrobial Activities of a Series of Disubstitutedarylazo-Barbituric- and Thiobarbituric Acid Derivatives

A simple, convenient and reproducible synthesis of several new disubstitutedarylazo-barbituric and thiobarbituric acids is described. The method involves condensation with urea and thiourea of 2,4-disubstituted phenylhydrazones formed from the reactions of the parent aniline diazonium salts with diethylmalonate. These new compounds were preliminary evaluated for their antimicrobial activities against five bacterial strains covering both (Gram positive and Gram negative bacterial strains) and two fungi. Three of the newly-synthesized compounds showed promising antimicrobial activities with no signs of human cells cytotoxicity.

DABCO-based ionic liquids: green and recyclable catalysts for the synthesis of barbituric and thiobarbituric acid derivatives in aqueous media

A new and straightforward method for the synthesis of 5-arylidine barbituric and thiobarbituric acids through a reaction between barbituric acid and its thio-analogue with aldehydes using [DABCO](SO3H)2(HSO4)2) as an efficient catalyst has been reported.

New Diethyl Ammonium Salt of Thiobarbituric Acid Derivative: Synthesis, Molecular Structure Investigations and Docking Studies.

The synthesis of the new diethyl ammonium salt of diethylammonium(E)-5-(1,5-bis(4-fluorophenyl)-3-oxopent-4-en-1-yl)-1,3-diethyl-4,6-dioxo-2-thioxohexaydropyrimidin-5-ide 3 via a regioselective Michael addition of N,N-diethylthiobarbituric acid 1 to dienone 2 is described. In 3, the carboanion of the thiobarbituric moiety is stabilized by the strong intramolecular electron delocalization with the adjacent carbonyl groups and so the reaction proceeds without any cyclization. The molecular structure investigations of 3 were determined by single-crystal X-ray diffraction as well as DFT computations. The theoretically calculated (DFT/B3LYP) geometry agrees well with the crystallographic data. The effect of fluorine replacement by chlorine atoms on the molecular structure aspects were investigated using DFT methods. Calculated electronic spectra showed a bathochromic shift of the π-π* transition when fluorine is replaced by chlorine. Charge decomposition analyses were performed to study possible interaction between the different fragments in the studied systems. Molecular docking simulations examining the inhibitory nature of the compound show an anti-diabetic activity with Pa (probability of activity) value of 0.229.

Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives.

2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines.

Synthesis and antimicrobial activity of novel imidazo[1,2-a]pyridinopyrimidine-2,4,6(1H,3H,5H)-triones and thioxopyrimidine-4,6(1H,5H)diones

A novel series of imidazo[1,2-a]pyridinopyrimidine-2,4,6(1H,3H,5H)-triones and thioxopyrimidine-4,6(1H,5H)diones were synthesized via multistep synthesis starting from 2-aminopyridine on cyclisation with phenacyl bromide followed by Vilsmeier–Haack and Knoevenagel condensation reactions. Structures of all the newly synthesized compounds were confirmed by their spectral and analytical studies. All the synthesized compounds were screened for their in vitro antimicrobial activity. Antibacterial activity results revealed that compounds 5f, 5i, and 5j have shown promising activity against S. pyogenes with ZOI ranging from 19 to 20 mm, compound 5g against P. aeruginosa (ZOI 19 mm) and 5f and 5h against S. aureus (ZOI 17, 18 mm) have shown good antibacterial activity. Among barbituric acid and thiobarbituric acid derivatives, thiobarbituric acid derivatives have shown maximum antibacterial activity. None of the compounds were found to be active at 150 µg/mL concentration against tested fungal strains.

Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies

In this study 36 new compounds were synthesized by condensing barbituric acid or thiobarbituric acid and respective anilines (bearing different substituents) in the presence of triethyl orthoformate in good yields. In vitro urease inhibition studies against jack bean urease revealed that barbituric acid derived compounds (1–9 and 19–27) were found to exhibit low to moderate activity however thiobarbituric acid derived compounds (10–18 and 28–36) showed significant inhibition activity at low micro-molar concentrations. Among the synthesized compounds, compounds (15), (12), (10), (36), (16) and (35) showed excellent urease inhibition with IC50 values 8.53±0.027, 8.93±0.027, 12.96±0.13, 15±0.098, 18.9±0.027 and 19.7±0.63μM, respectively, even better than the reference compound thiourea (IC50=21±0.011). The compound (11) exhibited comparable activity to the standard with IC50 value 21.83±0.19μM. In silico molecular docking studies for most active compounds (10), (12), (15), (16), (35) and (36) and two inactive compounds (3) and (6) were performed to predict the binding patterns.

Synthesis and docking studies of novel quinoline substituted thiobarbituric acid derivatives as potential therapeutic agents for type-II diabetes

Synthesis and docking studies of novel quinoline substituted thiobarbituric acid derivatives as potential therapeutic agents for type-II diabetes

Nimodipine: A Novel Protective Calcium Channel Blocker Against 3‐Nitropropionic Acid Induced Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disease characterized by motor, cognitive and psychological symptoms. Calcium channels play a critical role in the pathophysiology of HD via mediating oxidative and inflammatory damaging mechanisms. 3-nitropropionic acid (3NP) is an inhibitor of succinate dehydrogenase enzyme in the mitochondrial complex II and is used to induce HD like symptoms. This study was designed to investigate the effect of nimodipine, a novel calcium channel blocker on the behavioral and biochemical changes in a 3 NP model of HD in rats. 3-nitropropionic acid (10 mg/kg i.p.) for 14 days significantly reduced locomotor activity in open field in addition to muscle coordination and grip strength in the rotarod test. Furthermore, it impaired memory retention in Morris water maze and triggered a stereotypical behavior in rats. In both striatal and cortical homogenates 3NP reduced superoxide dismutase, non-enzymatic non-protein thiols while increased thiobarbituric acid derivatives and myeloperoxidase activity. Treatment with nimodipine (5mg/kg i.p.) for 14 days; 30 minute prior to 3NP, ameliorated the mentioned deleterious behavioral and biochemical alterations induced by 3NP. The results of this study suggest that calcium channel blockade may have protective effect against HD via modulating oxidative stress and inflammatory pathways.

Synthesis of some new fluorine substituted thiobarbituric acid derivatives as anti HIV1 and cyclin-dependent kinase 2 (CDK2) for cell tumor division: Part I

New potential enzyme inhibitors, fluorine-substituted thiobarbituric acid derivatives (2, 3, 9, 8 and 12) and their fused/isolated heterocyclic nitrogen systems (5, 6, 10 and 14) have been obtained from heterocyclization of fluorinated N , N ʹ-disubstituted thiourea (1, 7 and 11) with malonic acid followed by ring closure reactions with primary nitrogen reagents. Structures of the synthesized products have been deduced from their elemental analysis and spectral data. Anti-HIV-1 and inhibition of cyclin-dependent kinase2 (CDK2) for cell tumor division for the synthesized compounds were also evaluated.

Hydrogen bonding patterns in salts of derivatives of aminopyrimidine and thiobarbituric acid.

Three salts, namely 2-amino-4,6-dimethylpyrimidin-1-ium thiobarbiturate trihydrate (I), 2-amino-4,6-dimethoxypyrimidin-1-ium thiobarbiturate dihydrate (II) and 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidin-1-ium thiobarbiturate (III), were synthesized and characterized by IR and X-ray diffraction techniques. The primary interaction between the acid and base happens via N-H...O hydrogen bonds in (II) and (III), and via water-mediated N-H...OW and OW-HW...S in (I). The water molecules present in compound (I) form a (H2O)12 water cluster via water-water interactions. In all three compounds (I)-(III), thiobarbiturate anions form self-complementary pairs with a robust R2(2)(8) motif via a pair of N-H...O/N-H...S hydrogen bonds. They mimic the nucleobase base pairs by utilizing the same groups (thymine/uracil uses N3-H and C4=O8 groups during the formation of Watson-Crick and Hoogsteen base pairs with adenine). Compound (I) forms a water-mediated base pair through N-H...OW hydrogen bonds and forms an R4(2)(12) motif. The formation of N-H...S hydrogen bonds, water-mediated base pairs and water-water interactions in these crystal systems offers scope for these systems to be considered as a model in the study of hydration of nucleobases and water-mediated nucleobase base pairs in macromolecules.

Synthesis of novel 5-arylidene (thio)barbituric acid and evaluation of their urease inhibitory activity

A simple and practical method is described for the synthesis of novel 5-arylidene derivatives of barbituric and thiobarbituric acid. 2-Formylbenzoic acids reacted easily with (thio)barbituric acids in the presence of p-toluenesulfonic acid (p-TsOH) in MeOH/EtOH to obtain the title compound in good yields. Then, their urease inhibitory activity were evaluated in vitro and compared with hydroxyurea as the reference drug.

Synthesis, characterization and determination of third-order optical nonlinearity by cw z-scan technique of novel thiobarbituric acid derivative dyes

Donor acceptor chromophores were prepared by Knovenagel reaction of 1,3-diethyl-2-thiobarbituric acid with corresponding aldehydes in ethanol using pyridine as catalyst. The structures of newly synthesized compounds were evaluated by FT-IR, 1H NMR, 13C NMR, MS spectroscopy and purity of the compounds were confirmed by elemental analyses. The nonlinear refractive index n2 and nonlinear absorption coefficient β are measured for these dyes using the closed and open aperture z-scan technique with a cw He–Ne laser at 632.8nm. These values are found to be high and linearly dependent on the concentration.

Allosteric Inhibition of Epac

Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein. Using a bioluminescence resonance energy transfer-based assay (CAMYEL, cAMP sensor using YFP-Epac-Rluc), we assessed the predicted compounds for their ability to bind Epac and modulate its activity. We identified a thiobarbituric acid derivative, 5376753, that allosterically inhibits Epac activity and used Swiss 3T3 and HEK293 cells to test the ability of this compound to modulate the activity of Epac and PKA, as determined by Rap1 activity and vasodilator-stimulated phosphoprotein phosphorylation, respectively. Compound 5376753 selectively inhibited Epac in biochemical and cell migration studies. These results document the utility of a computational approach to identify a domain for allosteric regulation of Epac and a novel compound that prevents the activation of Epac1 by cAMP.

Abstract 1639: Development of novel thiobarbituric acid derivatives as potential cancer therapeutics

Abstract Chemotherapy drugs for the treatment of cancer are generally directed to inhibit the reproduction of malignant cells and killing cells, thereby preventing tumor growth or reducing tumor size. Many of these drugs develop resistance to tumor cells by different mechanisms. Therefore a significant clinical need exists for the development of additional chemotherapeutic agents that are toxic to a wide range of tumor cells, in particular tumors that are resistant to current treatments such as radiotherapy and chemotherapy. From recent past, it has been known that barbituric acid derivatives exhibit different biological activities such as anti-depressant, anti-convulsant, anti-viral and anti-cancer activities. Among them some thiobarbituric acid derivatives, such as merocyanine and merbarone have been proposed as possible modulators of apoptosis in several cancer cells including glioblastoma multiforme (GBM), lung, melanoma, leukemia, breast cancer, prostate cancer, and cervical cancer; albeit not particularly for cancers that are resistant to current therapy. We designed and synthesized novel thio- and seleno- barbituric derivatives by varying the substituents at N1, N3 (ethyl, methyl, allyl, and phenyl) and C5 tethered with dienyl and trienyl moieties attached with different substituents like phenyl, 2-furanyl, 2-thiophenyl, 1-naphthyl & 3-pyridyl. These compounds were tested against both chemotherapy sensitive and resistant, melanoma (UACC903 and CHL-1), GBM (U87-MG, T98G, and CCF-STTG1) , and lung cancer (A549, H460, H520and H69) cells. Most of these compounds reduced cell viability in a dose and time dependent manner. Among all the compounds ASR-198, ASR-199, ASR-243 and ASR-244 were most cytotoxic to both chemotherapy resistant and sensitive cells. In addition, these compounds triggered a dose dependent induction of apoptosis by activation of caspase-3 and PARP cleavage in melanoma cells. Overall compound ASR-198, having a 2-thiophen-dienyl substitution and C-5 position, emerged as the most efficacious compound in all three cancer cell lines. Interestingly its isosteric selenium analogs were relatively less cytotoxic. In summary, this structure-activity relationship study clearly indicates that more efficacious compounds, compared to existing thiobarbituric analogs, can be developed based on barbituric acid scaffold, by rational modifications of the chemo type compounds. Detailed results of these investigations will be presented. Citation Format: Srinivasa R. Ramisetti, Sang Y. Lee, Manoj K. Pandey, Shantu G. Amin, Arun K. Sharma. Development of novel thiobarbituric acid derivatives as potential cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1639. doi:10.1158/1538-7445.AM2014-1639

Efficient synthesis of novel benzylidene barbituric and thiobarbituric acid derivatives containing ethyleneglycol spacers

Knoevenagel condensation reaction of ethylene glycol-based aromatic aldehyde with barbituric acid derivatives in ethanol produced novel benzylidene barbituric and thiobarbituric acid derivatives which contain good yields of ethylene glycol spacers. Structures of the products were deduced from their IR, 1H-NMR, and 13C-NMR spectroscopy and mass spectra.

Synthesis and structure–activity relationship of thiobarbituric acid derivatives as potent inhibitors of urease

A series of thiobarbituric acid derivatives 1–27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1–27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC50 values 18.1±0.52, 16.0±0.45, 16.0±0.22, 14.3±0.27, 6.7±0.27, 10.6±0.17, 19.2±0.29, 18.2±0.76 and 1.61±0.18μM, respectively, much better than the standard urease inhibitor thiourea (IC50=21±0.11μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC50 values 21.4±1.04 and 21.5±0.61μM, 22.8±0.32, 25.2±0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure–activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and 1H NMR.

Abstract B06: Development of novel thiobarbituric acid derivative compounds for treatment of lung cancers.

Abstract Previously, we reported the identification of a cytotoxic chemotype compound CC-I (a derivative of thiobarbituric acid) that is effective against chemotherapy resistant glioblastomas (GBMs) and neuroblastoma in an in vitro cell culture and in vivo mouse tumor models. In this study, we determined the cytotoxicity of CC-I and structurally similar compounds along in lung cancers to determine whether CC-I is toxic to lung cancers and to identify additional analog compounds that could be more toxic than CC-I. We designed several CC-I analog compounds by manipulating functional substitutions at N1-, N3- and C5-positions (either furan ring or benzene ring) of CC-I. For example, the novel compounds were synthesized starting from substituted thioureas, key precursors for the synthesis of substituted thiobarbituric acids, and finally by condensing cinnamaldehyde (CMC-2 series: benzene ring compound) or trans-3-(2-furyl)-acrolein (CC-I series: furan ring compound) with appropriately substituted thiobarbituric acids in the presence of catalytic amounts of pyridine. We used MTS cell proliferation or SRB cytotoxicity assay to determine the toxic level of compounds on the human lung cancer cell lines (e.g., A549, H520, H460, H69). The data suggest that the functional group at N1-, N3- and C5 sites is important for toxicity. Among the compounds with similar structures, CC-I-v3 and CC-I-v4 are the two most cytotoxic compounds to lung cancer cells and also the cisplatin resistant lung cancer cell lines such as H1993 and H520. In some of the cell lines we investigated, CC-I-v1 and CMC-2 compounds showed greater toxicity than CC-I compound. Currently, we are studying the anti-tumor effect of these compounds in an in vivo nude mouse tumor model. In summary, this structure-activity study clearly indicates that we can develop more efficacious compounds compared to our original compounds by rational modifications of the chemotype compounds. [This project is supported by the Elsa U. Pardee Foundation] Citation Format: Sang Y. Lee, Srinivasa Ramisetti, Becky Slagle-Webb, Arun K. Sharma, James R. Connor. Development of novel thiobarbituric acid derivative compounds for treatment of lung cancers. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B06.

Synthesis of Some Novel Thiobarbituric Acid Derivatives and Their Related Compounds from Sulfa-Drug as Antiinflammatory

Synthesis of Some Novel Thiobarbituric Acid Derivatives and Their Related Compounds from Sulfa-Drug as Antiinflammatory

Synthesis of Some New Fluorine Substituted Thiobarbituricacid Derivatives as Anti HIV1 and Cyclin-Dependent Kinase 2 (CDK2) for Celltumer Division-Part II

In search for new potential inhibitors some new fluorine substituted thiobarbituric acid derivatives (2-4, 7, 8) and their fused/isolated heterobicyclic nitrogen systems (5, 6, 9, 10, 11, 12) have been synthesized from heterocyclization of fluorinated 1,3-diketoamine (1) with CS2 followed by ring closure reactions with primary nitrogen reagents. Structures of the targets have been established from elemental analysis and spectral data. Some synthesized systems have been evaluated as anti-HIV-1 and of cyclin-dependent kinase 2 (CDK2) for cell tumor division.

Novel 5‐Acetyl‐3‐aryl‐2‐thioxo‐dihydropyrimidine‐4,6(1H,5H)‐diones: One Pot Three‐Component Synthesis, Characterization and Antibacterial Activity

A series of new 5‐substituted thiobarbituric acid derivatives 5‐acetyl‐3‐aryl‐2‐thioxo‐dihydropyrimidine‐4,6(1H,5H)‐diones (2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h) were synthesized by one pot cyclocondensation of 1‐aroyl‐3‐arylthioureas with malonic acid in the presence of acetic anhydride. These compounds exist in equilibrium with their enolic tautomeric forms 5‐(1‐hydroxy ethylidene)‐3‐aryl‐2‐thioxo‐dihydropyrimidine‐4,6‐(1H,5H)‐diones. The structures were confirmed by spectroscopic data, elemental analyses and in case of the 2d by single crystal X‐ray diffraction data. A plausible mechanism for the formation of products is also proposed. Compounds (2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h) were evaluated for their preliminary antibacterial activity against a representative panel of Gram positive and Gram negative bacteria using levofloxacin as the reference drug and were found to exhibit promising activity. The tested compounds displayed different levels of inhibitory effects on bacterial strains. Compound 2b showed the maximum efficacy against pathogenic bacteria and was identified as the lead molecule for further structural modifications.