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.

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.

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.

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.

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.

Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design, synthesis, radiolabeling and biodistribution study.

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21-16.95 µM) superior to that of thiourea reference standard (IC50 = 20.04 µM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.

Synthesis and characterisation of thiobarbituric acid enamine derivatives, and evaluation of their α-glucosidase inhibitory and anti-glycation activity.

A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 264.07 ± 1.87 and 448.63 ± 2.46 µM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of α-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a-k, 5, and 6 showed significant to moderate anti-glycation activity (IC50 = 31.5 ± 0.81 to 554.76 ± 9.1 µM).

DNA topoisomerases as molecular targets for anticancer drugs.

The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.

New 1,2,3-triazole-(thio)barbituric acid hybrids as urease inhibitors: Design, synthesis, in vitro urease inhibition, docking study, and molecular dynamic simulation.

A new series of 1,2,3-triazole-(thio)barbituric acid hybrids 8a-n was designed and synthesized on the basis of potent pharmacophores with urease inhibitory activity. Therefore, these compounds were evaluated against Helicobacter pylori urease. The obtained result demonstrated that all the synthesized compounds, 8a-n, were more potent than the standard urease inhibitor, hydroxyurea. Moreover, among them, compounds 8a, 8c-e, 8g,h, and 8k,l exhibited higher urease inhibitory activities than the other standard inhibitor used: thiourea. Docking studies were performed with the synthesized compounds. Furthermore, molecular dynamic simulation of the most potent compounds, 8e and 8l, showed that these compounds interacted with the conserved residues Cys592 and His593, which belong to the active site flap and are essential for enzymatic activity. These interactions have two consequences: (a) blocking the movement of a flap at the entrance of the active site channel and (b) stabilizing the closed active site flap conformation, which significantly reduces the catalytic activity of urease. Calculation of the physicochemical and topological properties of the synthesized compounds 8a-n predicted that all these compounds can be orally active. The ADME prediction of compounds 8a-n was also performed.

Strategies to Improve the Thermo-Oxidative Stability of Sunflower Oil by Exploiting the Antioxidant Potential of Blueberries Processing Byproducts.

This research was conducted in order to establish the effectiveness of two freeze-dried extracts obtained from blueberry processing byproducts resulting from juice manufacturing compared to butylated hydroxytoluene (BHT) in delaying the lipid oxidation of sunflower oil subjected to high-temperature convective heating at 180 °C up to 12 h under simulated frying conditions. The fruits were harvested from spontaneous flora of two regions of Romania, Arieseni (Alba County) and Paltinis (Sibiu County) and the blueberry byproducts extracts (BBE) were noted according to the origin place as ABBE and PBBE. The progress of lipid thermo-oxidation was investigated in terms of peroxide value (PV), p-anisidine value (p-AV), the response of TBA-malondialdehyde interactions assessed by thiobarbituric acid (TBA) method, the total oxidation (TOTOX) value and inhibition of oil oxidation (IO). The recorded data highlighted that BBE exhibit a high inhibitory response on lipid thermo-oxidation. The inhibitory effect was concentration-dependent, thus, the degree of lipid oxidation was in reverse related to the BBE dose. The exposure of the oil samples supplemented with 800 ppm BBE (ABBE, PBBE) to a high-temperature heating for 12 h led to a significant decrease of the assessed indices compared to additives-free sunflower oil sample as follows: PV (46%; 45%), p-AV (21%; 17%), TOTOX (27%; 24%), TBA value (25%; 11%). Regarding the impact of the origin on the potential of BBE to inhibit the lipid oxidative degradation, it was noted that ABBE derived from blueberries grown in a region with a milder climate with moderate precipitations and higher temperatures showed a stronger inhibitory effect on lipid thermo-oxidation than PBBE. A moderate level of 500 ppm BBE inhibited the lipid oxidation similar to 200 ppm BHT. The reported results reveal that BBE represent efficient natural antioxidants that could be successfully applied to improve the thermo-oxidative stability of sunflower oil used in various high-temperature food applications.

Antioxidant Activity of Pastinaca sativa L. ssp. sylvestris [Mill.] Rouy and Camus Essential Oil.

In the last decade, there has been growing interest in the food industry in replacing synthetic chemicals with natural products with bioactive properties. This study's aims were to determine the chemical composition and the antioxidant properties of the essential oil of Pastianica sylvestris. The essential oil was isolated with a yield of 0.41% (w/v) by steam distillation from the dried seeds and subsequently analysed by GC-MS. Octyl acetate (78.49%) and octyl hexanoate (6.68%) were the main components. The essential oil exhibited an excellent activity for the inhibition of primary and secondary oxidation products for cold-pressed sunflower oil comparable with butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), which were evaluated using peroxide and thiobarbituric acid values. The antioxidant activity of the essential oil was additionally validated using DPPH radical scavenging (0.0016 ± 0.0885 mg/mL), and ß-carotene-linoleic acid bleaching assays. Also, the amounts of total phenol components (0.0053 ± 0.0023 mg GAE/g) were determined.

Xanthine Oxidase Inhibition and Anti-LDL Oxidation by Prenylated Isoflavones from Flemingia philippinensis Root.

Xanthine oxidase is a frontier enzyme to produce oxidants, which leads to inflammation in the blood. Prenylated isoflavones from Flemingia philippinensis were found to display potent inhibition against xanthine oxidase (XO). All isolates (1-9) inhibited XO enzyme with IC50 ranging 7.8~36.4 µM. The most active isoflavones (2-5, IC50 = 7.8~14.8 µM) have the structural feature of a catechol motif in B-ring. Inhibitory behaviors were disclosed as a mixed type I mode of inhibition with KI < KIS. Binding affinities to XO enzyme were evaluated. Fluorescence quenching effects agreed with inhibitory potencies (IC50s). The compounds (2-5) also showed potent anti-LDL oxidation effects in the thiobarbituric acid-reactive substances (TBARS) assay, the lag time of conjugated diene formation, relative electrophoretic mobility (REM), and fragmentation of apoB-100 on copper-mediated LDL oxidation. The compound 4 protected LDL oxidation with 0.7 µM in TBARS assay, which was 40-fold more active than genistein (IC50 = 30.4 µM).

N-Naphthoyl-substituted indole thio-barbituric acid analogs inhibit the helicase activity of the hepatitis C virus NS3.

The hepatitis C virus (HCV) represents a substantial threat to human health worldwide. The virus expresses a dual-function protein, NS3 having both protease and RNA helicase activities that are essential for productive viral replication and sustained infections. While viral protease and polymerase inhibitors have shown great successes in treating chronic HCV infections, drugs that specifically target the helicase activity have not advanced. A robust and quantitative 96-well plate-based fluorescent DNA unwinding assay was used to screen a class of indole thio-barbituric acid (ITBA) analogs using the full-length, recombinant HCV NS3, and identified three naphthoyl-containing analogs that efficiently inhibited NS3 helicase activity in a dose-dependent manner, with observed IC50 values of 21-24 µM. Standard gel electrophoresis helicase assays using radiolabeled duplex DNA and RNA NS3 substrates confirmed the inhibition of NS3 unwinding activity. Subsequent anisotropy measurements demonstrated that the candidate compounds did not disrupt NS3 binding to nucleic acids. Additionally, the rate of ATP hydrolysis and the protease activity were also not affected by the inhibitors. Thus, these results indicate that the three ITBA analogs containing N-naphthoyl moieties are the foundation of a potential series of small molecules capable of inhibiting NS3 activity via a novel interaction with the helicase domain that prevents the productive unwinding of nucleic acid substrates, and may represent the basis for a new class of therapeutic agents with the potential to aid in the treatment and eradication of hepatitis C virus.

A Small-Molecule Inhibitor of Human DNA Polymerase η Potentiates the Effects of Cisplatin in Tumor Cells.

Translesion DNA synthesis (TLS) performed by human DNA polymerase eta (hpol η) allows tolerance of damage from cis-diamminedichloroplatinum(II) (CDDP or cisplatin). We have developed hpol η inhibitors derived from N-aryl-substituted indole barbituric acid (IBA), indole thiobarbituric acid (ITBA), and indole quinuclidine scaffolds and identified 5-((5-chloro-1-(naphthalen-2-ylmethyl)-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (PNR-7-02), an ITBA derivative that inhibited hpol η activity with an IC50 value of 8 µM and exhibited 5-10-fold specificity for hpol η over replicative pols. We conclude from kinetic analyses, chemical footprinting assays, and molecular docking that PNR-7-02 binds to a site on the little finger domain and interferes with the proper orientation of template DNA to inhibit hpol η. A synergistic increase in CDDP toxicity was observed in hpol η-proficient cells co-treated with PNR-7-02 (combination index values = 0.4-0.6). Increased γH2AX formation accompanied treatment of hpol η-proficient cells with CDDP and PNR-7-02. Importantly, PNR-7-02 did not impact the effect of CDDP on cell viability or γH2AX in hpol η-deficient cells. In summary, we observed hpol η-dependent effects on DNA damage/replication stress and sensitivity to CDDP in cells treated with PNR-7-02. The ability to employ a small-molecule inhibitor of hpol η to improve the cytotoxic effect of CDDP may aid in the development of more effective chemotherapeutic strategies.

Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors.

Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.

The Effects of different nitrogen doses on antioxidant and antimicrobial activity of Stevia (Stevia rebaudiana Bert.).

In this study, the efficiency of the different nitrogen doses (0, 5, 10, 15 and 20 kg ha-1) on biological activity levels (antioxidant and antimicrobial activity) of Stevia rebaudiana Bert. was investigated. In addition, methanol extracts were obtained by maceration method from different doses of fertilizer applied stevia. The components in methanol extracts of plants were determined by gas chromatography-mass spectrometry (GC-MS) method. Antimicrobial activities of stevia extracts were investigated by microdilution method. The antioxidant activity evaluated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric thiocyanate (FTC), thiobarbituric acid (TBA), reducing power, total phenol content (TPC), and total flavonoid content (TFC) methods. According to the results, the fertilizer doses effects on antimicrobial activity of stevia were not made much difference. But in antioxidant activity, there were some variations in the activity-dependent on fertilizer amount.

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

Taurine, a ß-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.

Antioxidant capacity of cinnamon extract for palm oil stability.

BACKGROUND: Spices and their bioactive components are more promising attractions for their inclusion in diet-based regimes to improve human health. These are sources of natural antioxidants and play an important role in the chemoprevention of diseases and aging. The aim of the current study was to explore the antioxidant potential of cinnamon; a widely used spice throughout the world. METHODS: The current research was aimed to investigate the antioxidant potential of cinnamon extract. For the purpose, cinnamon sticks were procured from local super market, while palm oil was obtained from local oil industry. The resultant extract was analyzed for its antioxidant activity through total phenolic content (TPC), free radical scavenging activity (DPPH assay), and total antioxidant activity was measured by ferric reducing antioxidant power (FRAP) test. The shelf life of palm oil was checked by adding cinnamon extract in oil at different levels i.e., 0.05, 0.10, 0.15, 0.20 and 0.25%, to compare the antioxidant potential of the extract whereas, To acted as control and TBHA @ 0.1% was used as synthetic antioxidant in the oil samples. The oil samples were analyzed for rancidity check during storage (after every seven days for a storage period of four weeks). RESULTS: The results indicated that total phenolic contents (TPC); 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) values of cinnamon extract were as 355.01 ± 8.34 gallic acid equivalent per gram (mg GAE/g), 90.18 ± 2.12 (%) and 132.82 ± 3.12 (µmol/g), respectively. The oxidative parameters for treatments i.e., To, TBHA, T1, T2, T3, T4, T5 were recorded as peroxide value (2.61 ± 0.07, 2.42 ± 0.08, 2.57 ± 0.05, 2.56 ± 0.03, 2.54 ± 0.02, 2.54 ± 0.01, 2.46 ± 0.06 meq/kg, respectively), free fatty acids (0.601 ± 0.05, 0.522 ± 0.02, 0.580 ± 0.07, 0.572 ± 0.03, 0.56 ± 00.07, 0.552 ± 0.03, 0.536 ± 0.05%, respectively), TBA value (22.4 ± 1.45, 20.1 ± 0.73, 21.8 ± 0.42, 21.2 ± 1.56, 20.7 ± 0.48, 20.5 ± 0.59, 20.2 ± 0.91 µg/kg, respectively) and iodine value (52.82 ± 2.12, 52.71 ± 2.38, 52.68 ± 2.96, 52.97 ± 2.14, 52.93 ± 2.12, 53.15 ± 2.38, 52.71 ± 2.96, respectively). Overall, the statistical analysis indicated that all parameters regarding oil stability i.e., peroxide value (PV), free fatty acid content, (FFA) thiobarbituric acid (TBA) value and iodine value (IV) were significant with respect to treatments and storage. CONCLUSION: From the present study, it can be concluded that the cinnamon extract proved effective in reducing the lipid oxidation of palm oil and it can be successfully used in place of synthetic antioxidants in food preparations.

Syntheses of 4,6-dihydroxypyrimidine diones, their urease inhibition, in vitro, in silico, and kinetic studies.

A library of 4,6-dihydroxypyrimidine diones (1-35) were synthesized and evaluated for their urease inhibitory activity. Structure-activity relationships, and mechanism of inhibition were also studied. All compounds were found to be active with IC50 values between 22.6±1.14-117.4±0.73µM, in comparison to standard, thiourea (IC50=21.2±1.3µM). Kinetics studies on the most active compounds 2-7, 16, 17, 28, and 33 were performed to investigate their modes of inhibition, and dissociation constants Ki. Compounds 2, 3, 7, 16, 28, and 33 were found to be mixed-type of inhibitors with Ki values in the range of 7.91±0.024-13.03±0.013µM, whereas, compounds 4-6, and 17 were found to be non-competitive inhibitors with Ki values in the range of 9.28±0.019-13.05±0.023µM. In silico study was also performed, and a good correlation was observed between experimental and docking studies. This study is continuation of our previously reported urease inhibitory activity of pyrimidine diones, representing potential leads for further research as possible treatment of diseases caused by ureolytic bacteria.

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.