Antiurease screening of alkyl chain-linked thiourea derivatives: in vitro biological activities, molecular docking, and dynamic simulations studies.

Urease has become an important therapeutic target because it stimulates the pathogenesis of many human health conditions, such as pyelonephritis, the development of urolithiasis, hepatic encephalopathy, peptic ulcers, gastritis and gastric cancer. A series of alkyl chain-linked thiourea derivatives were synthesized to screen for urease inhibition activity. Structure elucidation of these compounds was done by spectral studies, such as IR, 1H NMR and 13C NMR, and MS analysis. In vitro urease enzyme inhibition assay revealed that compound 3c was the most potent thiourea derivative among the series with IC50 values of 10.65 ± 0.45 µM, while compound 3g also exhibited good activity with an IC50 value of 15.19 ± 0.58 µM compared to standard thiourea with an IC50 value of 15.51 ± 0.11 µM. The other compounds in the series possessed moderate to weak urease inhibition activity with IC50 values ranging from 20.16 ± 0.48 to 60.11 ± 0.78 µM. The most potent compounds 3c and 3g were docked to jack bean urease (PDB ID: 4H9M) to evaluate their binding affinities and to find the plausible binding poses. The docked complexes were refined through 100 ns-long MD simulations. The simulation results revealed that the average RMSD of 3c was less than that of the 3g compound. Furthermore, the radius of gyration plots for both complexes showed that 3c and 3g docking predicted binding modes did not induce any conformational change in the urease structure.

CustFRE: An annotated dataset for extraction of family relations from English text.

Meaningful Information extraction is an extremely important and challenging task due to the ever growing size of data. Training and evaluating automated systems for the task requires annotated datasets which are rarely available because of the great amount of human effort and time required for annotating data. The dataset described in this manuscript, CustFRE, is meant for systems that learn extracting family relations from text. Sentences having at least two persons have been collected from the internet. The texts are first processed using Stanford's NLP pipeline for basic NLP tagging. Next, a team of natural language processing experts annotated the dataset. All family relations among persons in the texts have been annotated, or a no_relation is annotated if no family relation between two persons can be inferred from the text. After annotation, the dataset was verified by an NLP expert for completeness and correctness. CustFRE contains in total 2,716 annotations. The dataset can be used by information extraction researchers as a benchmark for evaluating their systems, and can also be used for training and evaluating family relation extraction systems.

Development and evaluation of pH-sensitive biodegradable ternary blended hydrogel films (chitosan/guar gum/PVP) for drug delivery application.

pH responsive hydrogels have gained much attraction in biomedical fields. We have formulated ternary hydrogel films as a new carrier of drug. Polyelectrolyte complex of chitosan/guar gum/polyvinyl pyrrolidone cross-linked via sodium tripolyphosphate was developed by solution casting method. Fourier transform infrared spectroscopy, scanning electron microscopy and thermogravimetric analysis were conducted to examine the interactions between the polymeric chains, surface morphology and thermal stability, respectively. The swelling tests resulted that the swelling was reduced with the increase in the concentration of crosslinker due to the more entangled arrangement and less availability of pores in hydrogels. Ciprofloxacin hydrochloride was used as a model drug and its release in simulated gastric fluid, simulated intestinal fluid and phosphate buffer saline solution was studied. pH responsive behaviour of the hydrogels have subjected these hydrogels for drug release applications.

Folic acid-sulfonamide conjugates as antibacterial agents: design, synthesis and molecular docking studies.

Dihydrofolate reductase (DHFR) inhibitors, as antibacterial agents, contain pyrimidine, pteridine, and azine moieties among many other scaffolds. Folic acid (FA), with a pteridine ring and amine group, was used as our focus scaffold, which was then conjugated with sulfonamides to develop new conjugates. The novel synthesized conjugates were characterized using infrared spectroscopy, and 1H and 13C nuclear magnetic resonance (NMR) spectral studies and consequently screened for antimicrobial activities against bacterial strains with ampicillin as a positive control. Compound DS2 has the highest zone of inhibition (36.6 mm) with a percentage activity index (%AI) value of 122.8% against S. aureus and a minimum inhibitory concentration (MIC) of 15.63 µg mL-1. DHFR enzyme inhibition was also evaluated using the synthesized conjugates through in vitro studies, and inhibition assays revealed that compound DS2 exhibited a 75.4 ± 0.12% (mean ± standard error of the mean (SEM)) inhibition, which is comparable with the standard DHFR inhibitor trimethoprim (74.6 ± 0.09%). The compounds attached to the unsubstituted aryl moiety of the sulfonamides revealed better inhibition against the bacterial strains as compared to the methyl substituted aryl sulfonamides. Molecular docking studies of the novel synthesized conjugates were also performed on the DHFR enzyme to identify the plausible binding modes to explore the binding mechanisms of these conjugates.

Pegylation and Cell Based Bioassay of Human Interferon-α2b Along its Docking Studies and Effect on Plasma Half-Life.

BACKGROUND: Interferon-α2b is FDA approved drug for the treatment of chronic HCV and HBV, melanoma, AIDS-related KS, carcinomas, hairy cell leukemia and chronic myelogenous leukemia. However, administration of interferon-α2b to patients takes place thrice in a week due to short in vivo circulation half-life. OBJECTIVE: To extend the circulation half-life of IFN-α2b, it is conjugated with polyethylene glycol (PEG). However, PEGylation may results in reduction of its antiviral and antiproliferative activities but on the other side, it results in prolonged plasma half-life. METHODS: Human interferon-α2b was PEGylated with linear 20kDa methoxypolyethlene glycol (mPEG) Propionaldehyde (IFN-Ald20K), Y-Shaped 40kDa mPEG-Propionaldehyde (IFNAld40K), linear 20-kDa mPEG-Succinimidyl Succinate (IFN-NHS20K), and Y shaped 40kDa mPEG-Succinimidyl Succinate (IFN-NHS40K). Impact of PEG size, shape and PEGylation site was studied to establish their relationship with antiprolifetaive activities and serum retention time of PEGylated IFN-α2b. RESULT: RP-HPLC studies showed that larger PEGs (40kDa) increased the hydrodynamic volume and increased the serum retention time while antiproliferative activity in HepG2 cell line was decreased with increase in PEGylated interferon-α2b size. Molecular docking results also dictated the same effect that increase in PEGylated interferon-α2b size results in steric shielding of the receptor-binding site on interferon-α2b. IFN-Ald20K showed highest (45%) biological activity with serum half-life 40 hours while IFN-NHS40K showed least (7%) biological activity with serum halflife 56 hours. CONCLUSION: Thus, IFN-Ald40K with 12% residual activity and 62 hours of serum half-life proved to be a potent candidate for anticancer and antiviral effect with enhanced serum retention time.

Online clean-up setup for the determination of non-fluorescent acidic pharmaceutical drugs in complex biological samples.

Analysis of acidic pharmaceuticals in complex biological samples is a challenging and formidable task due to the existence of interfering constituents within the sample matrices. Therefore, in order to avoid analytical column clogging and suppression/enhancement of signals of the analyte of interest, herein a simple, cost-effective and quick online ion chromatography based clean-up setup was introduced. This system was further coupled with a cost-effective homemade photochemically induced fluorimetric (PIF) setup for direct online conversion of non-fluorescent acidic pharmaceutical drugs into their respective fluorescent species. This advantageous system was favorably applied for the determination of four non-fluorescent acidic compounds in two complex biological samples (human serum and oral fluid) with minimum labor and organic solvent consumption. At optimized conditions, the developed method has shown good sensitivity, selectivity, satisfactory recoveries (88.68-102.14%) and low limits of detection (0.35-8.10 µg/L) with minimum or zero matrix effect.

Synthesis and evaluation of solid lipid nanoparticles loaded with bovine serum albumin prepared by different methods.

.We evaluated the effect of different synthesis methods of solid lipid nanoparticles (SLNs) loaded with bovine serum albumin (BSA) on parameters including particle size, polydispersity index, loading capacity and % entrapment efficiency including release study. We investigated the binary fatty acids mixtures for test protein BSA. Different techniques were used as micro emulsion, ultrasound homogenization and double emulsification-evaporation for the BSA loading of SLNs. With the increase in BSA content from 0-10%, indicated an increase in the size and decrease in polydispersity index. The stability of SLNs loaded with BSA was examined by measuring the zeta potential and all formulations were found to be quite stable. Release study and kinetic models were applied to assess BSA release profile from different formulations of SLNs. The particle size of BSA loaded SLNs was reduced to 89.67 ± 4.88 nm when PEG 6000 and Brij were used as 0.25% and 1.5% of total formulation (F5). Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Fourier-transform infrared spectroscopy (FTIR) indicated the chemical stability of BSA which was used to load SLNs in different formulations. SLNs from the combinations of solid and liquid lipids had enhanced the physicochemical properties and permitted controlled release of BSA for up to 10 days. The study also evaluated the addition of polyethylene glycol which reduced the particles size and enhanced % entrapment efficiency. The release of BSA from SLNs was followed zero order rate kinetics and diffusion-controlled. Different mathematical models, i.e., zero order, first order, Higuchi and Korsmeyer-Peppas models were found best fit to BSA release profile of all formulations of SLNs.

Investigating Correlation between Protein Sequence Similarity and Semantic Similarity Using Gene Ontology Annotations.

Sequence similarity is a commonly used measure to compare proteins. With the increasing use of ontologies, semantic (function) similarity is getting importance. The correlation between these measures has been applied in the evaluation of new semantic similarity methods, and in protein function prediction. In this research, we investigate the relationship between the two similarity methods. The results suggest absence of a strong correlation between sequence and semantic similarities. There is a large number of proteins with low sequence similarity and high semantic similarity. We observe that Pearson's correlation coefficient is not sufficient to explain the nature of this relationship. Interestingly, the term semantic similarity values above 0 and below 1 do not seem to play a role in improving the correlation. That is, the correlation coefficient depends only on the number of common GO terms in proteins under comparison, and the semantic similarity measurement method does not influence it. Semantic similarity and sequence similarity have a distinct behavior. These findings are of significant effect for future works on protein comparison, and will help understand the semantic similarity between proteins in a better way.

Sulfonamides containing curcumin scaffold: Synthesis, characterization, carbonic anhydrase inhibition and molecular docking studies.

Curcumin is a multi-functional pharmacologically safe natural agent with proven cytoprotective effects to healthy human cells. In this study, a new series of sulfonamides with curcumin scaffold were synthesized, characterized and investigated for their carbonic anhydrase isoenzyme I (human) and II (bovine) isoforms. The structures of newly synthesized compounds were described by IR, 1H NMR and 13C NMR spectral data. Compound 14 showed the Ki value of 0.99 µM with highest inhibitory activity among all other synthesized compounds against hCA-I enzyme. Similarly enzyme kinetic studies of compound 14, 16 and 30 against bCAII enzyme showed Ki values of 0.71, 0.67 and 0.71 µM respectively. Our biological assays results showed that most of active compounds have similar inhibitory activities compared to standard acetazolamide drug. The molecular docking predicted binding modes showed that these compounds bind with hCA-1 enzyme in similar fashion.

Screening of curcumin-derived isoxazole, pyrazoles, and pyrimidines for their anti-inflammatory, antinociceptive, and cyclooxygenase-2 inhibition.

Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti-inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight. Additionally, cyclooxygenase-2 (COX-2) enzyme inhibition studies were performed through in vitro assays. In vivo anti-inflammatory studies showed that curcumin with pyrimidines was the most potent anti-inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7, 9, and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX-2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound. Molecular docking studies of 10, 11, and 12 compounds in human COX-2 binding site revealed the similar binding modes as that of other COX-2-selective inhibitors.

Comprehensive two-dimensional ion chromatography (2D-IC) coupled to a post-column photochemical fluorescence detection system for determination of neonicotinoids (imidacloprid and clothianidin) in food samples.

There are increasing concerns about the dietary risks of neonicotinoids (NNIs); therefore their sensitive and accurate determination in dietary products is indispensable. However, the complex composition of agricultural food matrixes makes their extraction and quantitative determination a challenging task. Realizing this need, we herein report a simple, cost-effective, selective and sensitive fluorescence analytical workflow for analyses of two non-fluorescent neonicotinoids imidacloprid (IMI) and clothianidin (CLT) in six complex food samples (honey, ginger, durian, apple, tomato, cucumber) by online clean-up of sample extracts using two-dimensional ion chromatography (2D-IC) and a subsequent online post column UV induced fluorescence detection system. This online clean-up setup has proven advantageous to improve the limit of detection, potentially diminish matrix effects, and reduce analysis time and labor. The developed method showed excellent analytical figures of merit including linearity, selectivity, repeatability, recovery, and resolution for analysis of IMI and CLT in food samples.

ChromBiSim: Interactive chromatin biclustering using a simple approach.

Combinatorial patterns of histone modifications sketch the epigenomic locale. Specific positions of these modifications in the genome are marked by the presence of such signals. Various methods highlight such patterns on global scale hence missing the local patterns which are the actual hidden combinatorics. We present ChromBiSim, an interactive tool for mining subsets of modifications from epigenomic profiles. ChromBiSim efficiently extracts biclusters with their genomic locations. It is the very first user interface based and multiple cell type handling tool for decoding the interplay of subsets of histone modifications combinations along their genomic locations. It displays the results in the forms of charts and heat maps in accordance with saving them in files which could be used for post analysis. ChromBiSim tested on multiple cell types produced in total 803 combinatorial patterns. It could be used to highlight variations among diseased versus normal cell types of any species. AVAILABILITY: ChromBiSim is available at (http://sourceforge.net/projects/chrombisim) in C-sharp and python languages.

Azomethines, isoxazole, N-substituted pyrazoles and pyrimidine containing curcumin derivatives: Urease inhibition and molecular modeling studies.

Curcumin has shown large number of pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its various derivatives for diverse biological functions. In this study, curcumin derived azomethine, isoxazole, pyrimidines and N-substituted pyrazoles were synthesized to investigate their urease enzyme inhibition. The structures of newly synthesized compounds were described by IR, MS, 1H NMR and 13C NMR spectral data. Urease enzyme inhibition was evaluated through in vitro assays in which compound 8b was found to be the most potent (IC50 = 2.44 ± 0.07 µM) among the tested compounds. The compounds with diazine ring system except the 4d showed better urease inhibition (IC50 = 11.43 ± 0.21-19.63 ± 0.28 µM) than the standard urease inhibitor thiourea (IC50 = 22.61 ± 0.23 µM). Similarly enzyme kinetics data revealed that compounds 3c-3e and 8b were competitive inhibitors with Ki values of 20.0, 19.87, 20.23 and 19.11 µM respectively while the compounds 4b, 4c and 4e were mixed type of inhibitors with Ki values 6.72, 19.69 and 6.72 µM respectively. Molecular docking studies were also performed to identify the plausible binding modes of the most active compounds.

OWL2 benchmarking for the evaluation of knowledge based systems.

OWL2 semantics are becoming increasingly popular for the real domain applications like Gene engineering and health MIS. The present work identifies the research gap that negligible attention has been paid to the performance evaluation of Knowledge Base Systems (KBS) using OWL2 semantics. To fulfil this identified research gap, an OWL2 benchmark for the evaluation of KBS is proposed. The proposed benchmark addresses the foundational blocks of an ontology benchmark i.e. data schema, workload and performance metrics. The proposed benchmark is tested on memory based, file based, relational database and graph based KBS for performance and scalability measures. The results show that the proposed benchmark is able to evaluate the behaviour of different state of the art KBS on OWL2 semantics. On the basis of the results, the end users (i.e. domain expert) would be able to select a suitable KBS appropriate for his domain.

Cyclic-RGD penta-peptides cRGDyK derivatized with cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes.

The present study reports the syntheses of half-sandwich complexes of the type [M(η5 -C5 H4 CONH-R)(CO)3 ] (M═Re,99m Tc;R═cyclic RGD peptide (cRGDyK) for potential imaging of αv ß3 integrin expression. The 99m Tc complex was prepared directly from the reaction of [99m Tc(OH2 )3 (CO)3 ]+ with cRGDyK, doubly conjugated to Thiele's acid [(C5 H5 COOH)2 ] in water. This approach extends the viability of metal-mediated retro Diels-Alder reactions for the preparation of small molecules such as linear tripeptides to a more complex cyclic peptide carrying a [(η5 -C5 H4 )99m Tc(CO)3 ] tag. The Diels-Alder product [(C5 H5 CONH-cRGDyK)2 ] was prepared from Thiele's acid via double peptide coupling. The Re-complex [Re(η5 -C5 H4 CONH-cRGDyK)(CO)3 ] was obtained by attaching [Re(η5 -C5 H4 COOH)(CO)3 ] directly to the N-terminus of cRGDyK. The identity of the 99m Tc-complex is confirmed by chromatographic comparison with the corresponding rhenium complex, fully characterized by spectroscopic techniques.

Synthesis, antibacterial and antifungal possession of amino acids containing sulfonamide moieties.

Sulfonamides were developed by the simple reaction of amino acid with p-toluenesulfonyl chloride and structures of the new products (2a, 2b and 2c) were confirmed by elemental and spectral analysis (FT-IR, 1HNMR and13CNMR). In vitro, developed compounds were screened for their antibacterial and antifungal activities against two sensitive bacteria belonging to both gram positive and gram-negative types and two fungi. The synthesized sulfonamides (2a, 2b, 2c) exhibited excellent antifungal activities against the tested fungi. Among the tested compounds 2a and 2b have marked activity against E. coli with zone of inhibition (mm) 22.3±0.11and 20.2±0.26 (MIC: 12.5µg/mL, 12.5µg/mL) and S. aureus with zone of inhibition (mm) 20.2±0.26 and 23.2±0.55 (MIC: 12.5µg/mL, 6.25µg/mL). Compound 2c is moderately efficient towards E. coli (zone of inhibition (mm) 14.2±0.64, MIC: 100µg/mL) and no activity against S. aureus.

Analytical Method for the Identification and Assay of Kojic Acid, Methylparaben, and Propylparaben in Cosmetic Products Using UPLC: Application of ISO 12787:2011 Standard.

A straightforward, fast UPLC method is developed for the identification and quantification of kojic acid (KA), methylparaben (MP), and propylparaben (PP) in 15 cosmetic products (skin whitening creams and lotions). Chromatographic separations for KA, MP, and PP were obtained in 3.5 min on an Acquity BEH-C18 column (100 × 2.1 mm, 1.7 µm particle size) as the stationary phase at 260 nm (diode-array detector), with the mobile phase comprising a mixture of 0.01 M dibasic potassium phosphate and methanol-acetonitrile (50 + 50). Validation studies were performed according to in-house established criteria. There was a linear function of concentrations over the range of 0.4-1.6 µg/mL for KA, MP, and PP. The LOQ for all components was 0.2 µg/mL using the S/N method. Good separation of analytes was observed, with acceptable values of resolution and tailing. The analytical approach defined in the ISO 12787:2011 standard ("Cosmetics-Analytical methods-Validation criteria for analytical results using chromatographic techniques") was used for the assay of cosmetic samples.

ChromClust: A semi-supervised chromatin clustering toolkit for mining histone modifications interplay.

Mining patterns of histone modifications interplay from epigenomic profiles are one of the leading research areas these days. Various methods based on clustering approaches and hidden Markov models have been presented so far with some limitations. Here we present ChromClust, a semi-supervised clustering tool for mining commonly occurring histone modifications at various locations of the genome. Applying our method to 11 chromatin marks in nine human cell types recovered 11 clusters based on distinct chromatin signatures mapping to various elements of the genome. Our approach is efficient in respect to time and space usage along with the added facility of maintaining database at the backend. It outperforms the existing methods with respect to mining patterns in a semi-supervised fashion mapping to various functional elements of the genome. It will aid in future by saving the resources of time and space along with efficiently retrieving the hidden interplay of histone combinations.

Synthesis, antimicrobial and antifungal possessions of tramadol esters: In vitro studies.

Tramadol esters were prepared by refluxing equimolar concentration of tramadol with leucine and asparagine separately with methanol, sulphuric acid and phthalic anhydride for 10 hours and temperature was maintained at 75°C. After refluxing, the colour of sample solutions were changed from colorless to yellow, blank solution was prepared in the same way as the sample solution except the Tramadol. Both the products and blank were neutralized with sodium carbonate and excess of sodium bicarbonate was precipitated as sodium sulphate, which was washed with acetone. The structures of both the products were confirmed with spectral data (FT-IR, 1HNMR and 13CNMR). Antimicrobial and anti-fungal property of derivative of analgesic tramadol drug was tested with one fungus and three sensitive bacteria belonging to both gram positive and gram-negative types. Esterified product of tramadol with leucine and asparagine showed moderate activity against Escherichia coli and Tricophyton rubrum. Both the products showed marked activity against Staphylococcus aureus and found no activity against Salmonella spp.

MCaVoH: A toolkit for mining, classification and visualization of human microbiota.

Human body is the home for a large number of microbes. The complexity of enterotype depends on the body site. Microbial communities in various samples from different regions are being classified on the basis of 16S rRNA gene sequences. With the improvement in sequencing technologies various computational methods have been used for the analysis of microbiome data. Despite several available machine learning techniques there is no single platform available which could provide several techniques for clustering, multiclass classification, comparative analysis and the most significantly the identification of the subgroups present within larger groups of human microbial communities. We present a tool named MCaVoH for this purpose which performs clustering and classification of 16S rRNA sequence data and highlight various groups. Our tool has an added facility of biclustering which produces local group of communities present within larger groups (clusters). The core objective of our work was to identify the interaction between various bacterial species along with monitoring the composition and variations in microbial communities. MCaVoH also evaluates the performance and efficiency of different techniques using comparative analysis. The results are visualized through different plots and graphs. We implemented our tool in MATLAB. We tested our tool on several real and simulated 16S rRNA data sets and it outperforms several existing methods. Our tool provides a single platform for using multiple clustering, classification algorithms, local community identification along with their comparison which has not been done so far. Tool is available at https://sourceforge.net/projects/mcavoh/.