New Hybrid Ethylenediurea (EDU) Derivatives and Their Phytoactivity.

Natural and synthetic phytohormones are widely used in agriculture. The synthetic cytokinin ethylenediurea (EDU) induces protection in plants against ozone phytotoxicity. In our study, new hybrid derivatives of EDU were synthesized and tested for phytoactivity. The germination potential (Gp), germination of seeds (G), and relative water content in leaves (RWC), characterizing the drought resistance of plants, were determined. The results of laboratory studies showed that EDU and its hybrid derivatives have a positive effect on root length, the growth and development of shoots, as well as the ability of plants to tolerate stress caused by a lack of water.

Fluorescent-Tagged Antiscalants-The New Materials for Scale Inhibition Mechanism Studies, Antiscalant Traceability and Antiscaling Efficacy Optimization during CaCO3 and CaSO4·2H2O Scale Formation.

Equipment scaling leads to reduced production efficiency in a wide range of industrial applications worldwide. Various antiscaling agents are currently commonly used to mitigate this problem. However, irrespective of their long and successful application in water treatment technologies, little is known about the mechanisms of scale inhibition, particularly the localization of scale inhibitors on scale deposits. The lack of such knowledge is a limiting factor in the development of applications for antiscalants. Meanwhile, fluorescent fragments integrated into scale inhibitor molecules have provided a successful solution to the problem. The focus of this study is, therefore, on the synthesis and investigation of a novel fluorescent antiscalant: (2-(6-morpholino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)yl)ethylazanediyl)bis(methylenephosphonic acid) (ADMP-F) which is an analog of the commercial antiscalant: aminotris(methylenephosphonic acid) (ATMP). ADMP-F has been found to effectively control the precipitation of CaCO3 and CaSO4 in solution and is a promising tracer for organophosphonate scale inhibitors. ADMP-F was compared with two other fluorescent antiscalants-polyacrylate (PAA-F1) and bisphosphonate (HEDP-F)-and was found to be highly effective: PAA-F1 > ADMP-F >> HEDP-F (CaCO3) and PAA-F1 > ADMP-F > HEDP-F (CaSO4·2H2O). The visualization of the antiscalants on the deposits provides unique information on their location and reveals differences in the "antiscalant-deposit" interactions for scale inhibitors of different natures. For these reasons, a number of important refinements to the mechanisms of scale inhibition are proposed.

Patient-Reported Outcome Measures in Atopic Dermatitis and Chronic Urticaria Are Underused in Clinical Practice.

BACKGROUND: Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. They are crucial for monitoring atopic dermatitis (AD) and chronic urticaria (CU) in clinical practice, but there are unmet needs and knowledge gaps regarding their use in clinical practice. OBJECCTIVE: We investigated the global real-world use of AD and CU PROMs in allergology and dermatology clinics as well as their associated local and regional networks. METHODS: Across 72 specialized allergy and dermatology centers and their local and regional networks, 2,534 physicians in 73 countries completed a 53-item questionnaire on the use of PROMs for AD and CU. RESULTS: Of 2,534 physicians, 1,308 were aware of PROMs. Of these, 14% and 15% used PROMs for AD and CU, respectively. Half of physicians who use PROMs do so only rarely or sometimes. Use of AD and CU PROM is associated with being female, younger, and a dermatologist. The Patient-Oriented Scoring Atopic Dermatitis Index and Urticaria Activity Score were the most common PROMs for AD and CU, respectively. Monitoring disease control and activity are the main drivers of the use of PROMs. Time constraints were the primary obstacle to using PROMs, followed by the impression that patients dislike PROMs. Users of AD and CU PROM would like training in selecting the proper PROM. CONCLUSIONS: Although PROMs offer several benefits, their use in routine practice is suboptimal, and physicians perceive barriers to their use. It is essential to attain higher levels of PROM implementation in accordance with national and international standards.

Quinolinate salvage and insights for targeting NAD biosynthesis in group A streptococci.

The essential coenzyme NAD plays important roles in metabolic reactions and cell regulation in all organisms. As such, NAD synthesis has been investigated as a source for novel antibacterial targets. Cross-species genomics-based reconstructions of NAD metabolism in group A streptococci (GAS), combined with focused experimental testing in Streptococcus pyogenes, led to a better understanding of NAD metabolism in the pathogen. The predicted niacin auxotrophy was experimentally verified, as well as the essential role of the nicotinamidase PncA in the utilization of nicotinamide (Nm). PncA is dispensable in the presence of nicotinate (Na), ruling it out as a viable antibacterial target. The function of the "orphan" NadC enzyme, which is uniquely present in all GAS species despite the absence of other genes of NAD de novo synthesis, was elucidated. Indeed, the quinolinate (Qa) phosphoribosyltransferase activity of NadC from S. pyogenes allows the organism to sustain growth when Qa is present as a sole pyridine precursor. Finally, the redundancy of functional upstream salvage pathways in GAS species narrows the choice of potential drug targets to the two indispensable downstream enzymes of NAD synthesis, nicotinate adenylyltransferase (NadD family) and NAD synthetase (NadE family). Biochemical characterization of NadD confirmed its functional role in S. pyogenes, and its potential as an antibacterial target was supported by inhibition studies with previously identified class I inhibitors of the NadD enzyme family. One of these inhibitors efficiently inhibited S. pyogenes NadD (sp.NadD) in vitro (50% inhibitory concentration [IC(50)], 15 µM), exhibiting a noncompetitive mechanism with a K(i) of 8 µM.

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity.

Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In "proof of concept" experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 muM IC(50) and having no effect on human ACC1 at 100 muM.

Enhancement of Polyacrylate Antiscalant Activity during Gypsum Deposit Formation with the Pretreatment of Aqueous Solutions with Spruce Wood Shavings.

Considerable efforts are made worldwide to reduce inorganic scale in reverse osmosis plants, boilers and heat exchangers, evaporators, industrial water systems, geothermal power plants and oilfield applications. These include the development of new environmentally friendly antiscalants and the improvement of conventional ones. The present report is dedicated to the unconventional application of spruce wood shavings in combination with polyacrylate (PAA-F1) in a model case of gypsum scale formation. The electrical conductivity of freshly prepared gypsum solutions with a saturation SI = 2.3 and a concentration of 0.05 mol·dm-3 was analyzed over time at 25°C. It is demonstrated that the small amounts of wood shavings (0.1% by mass) alone, after being in contact with CaCl2 and Na2SO4 stock solutions for 15 min, increase the induction time tind by 25 min relative to the blank experiment (tindblank). In the presence of PAA-F1 (0.1 mg·dm-3), the difference Δtind = tind - tindblank constitutes 110 min, whereas the sequential treatment of the stock solutions with the shavings followed by PAA-F1 injection gives Δtind = 205 min. The observed synergism is associated with the selective removal of colloidal Fe(OH)3solid and Al(OH)3solid nanoimpurities from the stock solutions via their sorption to the well-developed surface of wood. Wood shavings therefore represent a very promising and environmentally friendly material that can significantly improve the effectiveness of conventional antiscalants.

Application and Visualization of Fluorescent-Tagged Antiscalants in Electrodialysis Processing of Aqueous Solutions Prone to Gypsum Scale Deposition.

Membrane scaling is a serious problem in electrodialysis. A widely used technique for controlling scale deposition in water treatment technologies is the application of antiscalants (AS). The present study reports on gypsum scale inhibition in electrodialysis cell by the two novel ASs: fluorescent-tagged bisphosphonate 1-hydroxy-7-(6-methoxy-1,3-dioxo-1Hbenzo[de]isoquinolin-2(3H)-yl)heptane-1,1-diyl-bis(phosphonic acid), HEDP-F and fluorescein-tagged polyacrylate, PAA-F2 (molecular mass 4000 Da) monitored by chronopotentiometry and fluorescent microscopy. It was found that cation-exchange membrane MK-40 scaling is sufficiently reduced by both ASs, used in 10-6 mol·dm-3 concentrations. PAA-F2 at these concentrations was found to be more efficient than HEDP-F. At the same time, PAA-F2 reveals gypsum crystals' habit modification, while HEDP-F does not noticeably affect the crystal form of the deposit. The strong auto-luminescence of MK-40 hampers visualization of both PAA-F2 and HEDP-F on the membrane surface. Nevertheless, PAA-F2 is proved to localize partly on the surface of gypsum crystals as a molecular adsorption layer, and to change their crystal habit. Crystal surface coverage by PAA-F2 appears to be nonuniform. Alternatively, HEDP-F localizes on the surface of a deposit tentatively in the form of [Ca-HEDP-F]. The proposed mechanisms of action are formulated and discussed. The application of antiscalants in electrodialysis for membrane scaling mitigation is demonstrated to be very promising.

A Case Study of Calcium Carbonate Crystallization during Reverse Osmosis Water Desalination in Presence of Novel Fluorescent-Tagged Antiscalants.

Calcium carbonate scaling in reverse osmosis (RO) desalination process is studied in the presence of two novel fluorescent-tagged scale inhibitors 1,8-naphthalimide-tagged polyacrylate (PAA-F1) and 1-hydroxy-7-(6-methoxy-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)heptane-1,1-diyl-bis(phosphonic acid) (HEDP-F) by fluorescent microscopy (FM) and scanning electron microscopy (SEM). Both antiscalants diminished the mean size of calcite crystals relative to the blank experiment. The behavior and localization of HEDP-F and PAA-F1 during calcite scale formation on membrane surface was found to be significantly different from the distribution in similar RO experiments with gypsum, reported earlier. In the former case, both antiscalants are concentrated exactly on the surface of calcium carbonate crystals, while in the latter one they form their own phases (Ca-HEDP-F and Ca-PAA-F1) and are not detected on gypsum scale. The difference is interpreted in terms of interplay between background calcium concentration and sparingly soluble calcium salts' solubility. HEDP-F reveals slightly higher efficiency than PAA-F1 against calcite scale formation, while PAA-F exhibits a higher ability to change calcite morphology. It is demonstrated that there is a lack of correlation between antiscaling efficacy and ability of antiscalant to change calcium carbonate morphology in a particular case study. An application of fluorescent-tagged antiscalants in RO experiments provides a unique possibility to track the scale inhibitor molecules' localization during calcite scale formation. Fluorescent-tagged antiscalants are presumed to become a very powerful tool in membrane scaling inhibition studies.

Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists.

Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors.

Synthesis of cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines and their evaluation as 5-HT6 receptor antagonists.

Synthesis and biological evaluation of 1 ('angular') and 2 ('linear') cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines as novel ligands of the 5-HT(6) receptors are disclosed. The new compounds 1 and 2 are highly selective antagonists of the receptor with sub-nanomolar affinities (K(i)<1 nM). In its structure, this new chemotype lacks a basic ionizable side chain, which is considered as the characteristic feature of the 5-HT(6) receptor antagonists pharmacophore model.

Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists.

A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines were prepared and their 5-HT6 receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were evaluated. 3-[(3-chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC50=29.0 nM) and 3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,28} demonstrated the greatest affinity in a 5-HT6 receptor radioligand binding assay (Ki=1.7 nM). A screening of 5-HT2A and 5-HT2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines are highly selective 5-HT6 receptor ligands.

Solution phase parallel synthesis of substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines: selective serotonin 5-HT(6) receptor antagonists.

Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT(6) receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT(6)R antagonists. The most active 5-HT(6)R antagonists have IC(50) <100 nM in a functional assay, and K(i) <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.

Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists.

Synthesis, biological evaluation and structure-activity relationships for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, gamma-carbolines 3{8} and 3{14} have been identified as potent small molecule antagonists of histamine H(1) (IC(50)=0.1 microM) and serotonin 5-HT(6) (IC(50)=0.37 microM) receptors, respectively.

Synthesis and biological evaluation of novel 5,8-disubstituted-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indoles as 5-HT(6) and H(1) receptors antagonists.

Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-gamma-carboline 5b (2,8-dimethyl-5-[cis-2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H(1) and serotonin 5-HT(6) receptors (IC(50) < 0.45 microM and IC(50) = 0.73 microM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.

Screening for caspase-3 inhibitors: effect of a reducing agent on identified hit chemotypes.

When studying cysteinyl proteases in general and caspases in particular, it is generally accepted that a reaction buffer must contain a reducing agent to prevent essential cysteinyl groups from spontaneous oxidation. Dithiothreitol (DTT) and beta-mercaptoethanol (beta-MCE) are 2 of the most broadly used reducing agents. While screening a library of small molecules against caspase-3, the authors have found that the nature of the reducing agent used, DTT or beta-MCE, dramatically affects screening results and leads to identification of nonoverlapping hits. Screening in DTT-containing buffer revealed few novel classes of small molecules that selectively and reversibly inhibit caspase-3 but failed to identify isatin sulfonamides recently found to be potent and selective caspase-3 inhibitors (false negatives). On the other hand, screening in the presence of beta-MCE failed to identify a series of hit compounds, 1,3-dioxo-2,3-dichloro-1H-pyrrolo[3,4-c]quinolines, discovered with DTT, whereas isatin sulphonamides in these conditions exhibited strong caspase-3 inhibition. In this work, the authors show that thiol-containing reducing agents can affect catalytic activity of caspase-3 and modify its thermostability in a redox-potential-independent manner. The authors speculate that the differential structural modifications of caspase-3 seen with different reducing agents represent structurally different caspase-3 conformations and are responsible for its differential sensitivity to small molecules of different chemotypes. Hence, selection of the reducing agent may dramatically affect the quality of high-throughput screening campaigns.

Screening for caspase-3 inhibitors: a new class of potent small-molecule inhibitors of caspase-3.

From the authors' 650,000 compound collection, they have selected approximately 15,000 potential small-molecule protease inhibitors, which were subjected to high-throughput screening against caspase-3. The screening yielded a series of hits that belong to 11 different scaffolds. Based on the structure of one of the hits, a new class of the small-molecule inhibitors with a double electrophilic warhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and anti-apoptosis assays. Mechanistic analysis of a representative compound of this class, CD-001-0011, showed that the compound exhibited a high potency (IC (50)=130 nM), was reversible though noncompetitive, and had a broad selectivity profile to other caspases belonging to groups I to III. The compound was effective in preventing staurosporine induced apoptosis in a few cell lines and retinoic acid-induced apoptosis in zebrafish.

Recent progress in development of non-ATP competitive small-molecule inhibitors of protein kinases.

The majority of marketed and late stage development kinase inhibitors are reported to be ATP-competitive. As a result, many promising drug candidates display non-specific activity that results in undesired physiological effects. There is growing interest towards non-ATP competitive kinase inhibitors, as they are expected to yield highly specific and efficacious molecules devoid of non-mechanistic toxicity. Recent developments in this area are summarized in our review.

Natural products as templates for bioactive compound libraries: synthesis of biaryl derivatives of (+/-)-vasicine.

A reliable and high-yielding procedure for preparation of 7-aryl and 7-heteroaryl derivatives of (+/-)-vasicine in two steps from the naturally occurring material is described. This protocol broadens the chemical space for selective modifications of the vasicine tricyclic structure, thereby making it a valuable starting point for the development of novel compound libraries with potentially beneficial biological profiles.

Exploring the chemogenomic knowledge space with annotated chemical libraries.

The recent human genome initiatives have led to the discovery of a multitude of genes that are potentially associated with various pathologic conditions and, thus, have opened new horizons in drug discovery. Simultaneously, annotated chemical libraries have emerged as information-rich databases to integrate biological and chemical data. They can be useful for the discovery of new pharmaceutical leads, the validation of new biotargets and the determination of the structural basis of ligand selectivity within target families. Annotated libraries provide a strong information basis for computational design of target-directed combinatorial libraries, which are a key component of modern drug discovery. Today, the rational design of chemical libraries enhanced with chemogenomics data is a new area of progressive research.