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Compound Classes (compound + class)
Selected AbstractsNMR and UPLC-qTOF-MS/MS characterisation of novel phenylethanol derivatives of phenylpropanoid glucosides from the leaves of strawberry (Fragaria × ananassa cv. Jonsok)PHYTOCHEMICAL ANALYSIS, Issue 5 2009Kati Hanhineva Abstract Introduction Strawberry (Fragaria × ananassa) is rich in polyphenols, particularly anthocyanins, flavonols, condensed tannins and ellagic tannins. In addition to the fruits, the leaves of strawberry also contain a wide range of phenolic compound classes, but have not been investigated to the same extent as the fruit. Objective To characterise a metabolite group present in the leaves of strawberry, that was not amenable for identification based on earlier information available in the literature. Methodology Methanolic extracts of strawberry leaves were analysed by UPLC-qTOF-MS/MS and iterative quantum mechanical NMR spectral analysis. Results The structures of phenylethanol derivatives of phenylpropanoid glucosides Eutigoside A ( F4) and its two isomeric forms 2-(4-hydroxyphenyl)ethyl-[6- O -(Z)-coumaroyl]- ,- d -glucopyranoside ( F6) and 4-(2-hydroxyethyl)phenyl-[6- O -(e)-coumaroyl]- ,- d -glucopyranoside ( F1) were resolved by NMR and UPLC-qTOF-MS/MS. In addition, two other derivatives of phenylpropanoid glucosides similar to Eutigoside A but possessing different phenolic acid moieties, namely Grayanoside A ( F5) and 2-(4-hydroxyphenyl)ethyl-[6- O -(e)-caffeoyl]- ,- d -glucopyranoside ( F14), were similarly identified. Also, accurate characteristic coupling constants for the subunits are reported and their usefulness in structural analysis is highlighted. Conclusion Chemical analysis of the leaves of strawberry (Fragaria × ananassa cv. Jonsok) resulted in the identification of a compound class, phenylethanol derivatives of phenylpropanoid glycosides, not previously found in strawberry. Copyright © 2009 John Wiley & Sons, Ltd. [source] Off-Target Effects Related to the Phosphorothioate Modification of Nucleic AcidsCHEMMEDCHEM, Issue 8 2010Johannes Winkler Dr. Abstract Phosphorothioate antisense oligonucleotides have been widely used in clinical studies for rational sequence-specific gene silencing. However, several sequence-unspecific off-target effects have been recently described for this compound class. In contrast to siRNA-mediated knockdown of the same gene, the bcl-2 -targeted oblimersen (Genasense, G3139) downregulates a number of proteins involved in apoptotic resistance and several glycolytic enzymes in 607B human melanoma cells. Regardless of their target, phosphorothioate-modified antisense and siRNA compounds, but not oligonucleotides with a phosphodiester backbone, resulted in a similar impact on the proteome. Unspecifically downregulated proteins include cancer markers involved in apoptotic resistance and endoplasmatic reticulum (ER) stress such as the 78,kDa glucose regulated protein (GRP,78), protein disulfide isomerase,A3 (PDIA3, GRP,58), calumenin, and galectin-1, as well as the glycolytic enzymes triose phosphate isomerase, glyceraldehyde phosphodehydrogenase, and phosphoglycerate mutase. The depletion of the glycolytic enzymes is reflected by a decrease in L -lactate production, indicating a partial reversal of the Warburg effect. Compared with other phosphorothioate oligonucleotides, oblimersen generally led to a more pronounced effect both in terms of the number of influenced proteins and the extent of downregulation, suggesting a synergistic effect of Bcl-2 downregulation. [source] Design, Synthesis, and Biological Evaluation of Caprolactam-Modified Bengamide AnaloguesCHEMMEDCHEM, Issue 1 2008Gang Liu Dr. A series of potent, water-soluble N-substituted bengamide analogues were discovered through diverse derivatives of the caprolactam unit of bengamide. Important SAR information was also gathered, and is different from previously reported SARs of this compound class. We therefore present a new view of bengamide natural products. [source] Unexpected Novel Binding Mode of Pyrrolidine-Based Aspartyl Protease Inhibitors: Design, Synthesis and Crystal Structure in Complex with HIV ProteaseCHEMMEDCHEM, Issue 1 2006Edgar Specker Dr. Abstract At present nine FDA-approved HIV protease inhibitors have been launched to market, however rapid drug resistance arising under antiviral therapy calls upon novel concepts. Possible strategies are the development of ligands with less peptide-like character or the stabilization of a new and unexpected binding-competent conformation of the protein through a novel ligand-binding mode. Our rational design of pyrrolidinedimethylene diamines was inspired by the idea to incorporate key structural elements from classical peptidomimetics with a non-peptidic heterocyclic core comprising an endocyclic amino function to address the catalytic aspartic acid side chains of Asp,25 and 25,. The basic scaffolds were decorated by side chains already optimized for the recognition pockets of HIV protease or cathepsin,D. A multistep synthesis has been established to produce the central heterocycle and to give flexible access to side chain decorations. Depending on the substitution pattern of the pyrrolidine moiety, single-digit micromolar inhibition of HIV-1 protease and cathepsin,D has been achieved. Successful design is suggested in agreement with our modelling concepts. The subsequently determined crystal structure with HIV protease shows that the pyrrolidine moiety binds as expected to the pivotal position between both aspartic acid side chains. However, even though the inhibitors have been equipped symmetrically by polar acceptor groups to address the flap water molecule, it is repelled from the complex, and only one direct hydrogen bond is formed to the flap. A strong distortion of the flap region is detected, leading to a novel hydrogen bond which cross-links the flap loops. Furthermore, the inhibitor addresses only three of the four available recognition pockets. It achieves only an incomplete desolvation compared with the similarly decorated amprenavir. Taking these considerations into account it is surprising that the produced pyrrolidine derivatives achieve micromolar inhibition and it suggests extraordinary potency of the new compound class. Most likely, the protonated pyrrolidine moiety experiences strong enthalpic interactions with the enzyme through the formation of two salt bridges to the aspartic acid side chains. This might provide challenging opportunities to combat resistance of the rapidly mutating virus. [source] Evaluation of CE methods for global metabolic profiling of urineELECTROPHORESIS, Issue 14 2010Rawi Ramautar Abstract In this study, the usefulness of noncovalently coated capillaries with layers of charged polymers is investigated to obtain global electrophoretic profiles of urinary metabolites covering a broad range of different compound classes in a highly repeatable way. Capillaries were coated with a bilayer of polybrene (PB) and poly(vinyl sulfonate) (PVS), or with a triple layer of PB, dextran sulfate (DS) and PB. The bilayer and triple layer coatings were evaluated at acidic (pH 2.0) and alkaline (pH 9.0) separation conditions, thereby providing separation conditions for basic and acidic compounds. A representative metabolite mixture and spiked urine samples were used for the evaluation of the four CE methods. Migration time repeatability (RSD<2%) and plate numbers (N, 100,000,400,000) were similar for the test compounds in all CE methods, except for some multivalent ions that may exhibit adsorption to oppositely charged coatings. The analysis of cationic compounds with the PB-DS-PB CE method at low pH (i.e. after the EOF time) provided a larger separation window and number of separated peaks in urine compared to the analysis with the PB-PVS CE method at low pH (i.e. before the EOF time). Approximately, 600 molecular features were detected in rat urine by the PB-DS-PB CE-MS method whereas about 300 features were found with the PB-PVS CE-MS method. This difference can be attributed to reduced comigration of compounds with the PB-DS-PB CE-MS method and a related decrease of ion suppression. With regard to the analysis of anionic compounds by CE-MS, in general analyte responses were significantly lower than that for cationic compounds, most probably due to less efficient ionization and to ion suppression effects caused by the background electrolyte. Hence, further optimization is required for the sensitive CE-MS analysis of anionic compounds in body fluids. It is concluded that the selection of a CE method for profiling of cationic metabolites in urine depends on the purpose of the study. For high-throughput analyses, the PB-PVS CE-MS method is favored whereas the PB-DS-PB CE-MS method provides a more information-rich metabolic profile, but at the cost of prolonged analysis time. [source] Achiral and chiral separations using MEKC, polyelectrolyte multilayer coatings, and mixed mode separation techniques with molecular micellesELECTROPHORESIS, Issue 6 2010Candace A. Luces Abstract Mixed mode (MM) separation using a combination of MEKC and polyelectrolyte multilayer (PEM) coatings is herein reported for the separation of achiral and chiral analytes. Many analytes are difficult to separate by MEKC and PEM coatings alone. Therefore, the implementation of a MM separation provides several advantages for overcoming the limitations of these well-established methods. In this study, it was observed that achiral separations using MEKC and PEM coatings individually resulted in partial resolution of eight very similar aryl ketones when the molecular micelle (sodium poly(N -undecanoyl- L -glycinate)) concentration was varied from 0.25 to 1.00%,w/v and the bilayer number varied from 2 to 4. However, when MM separation was introduced, baseline resolution was achieved for all eight analytes. In the case of chiral separations, temazepam, aminoglutethimide, benzoin, benzoin methyl ether, and coumachlor were separated using the three separation techniques. For chiral separations, the chiral molecular micelle, sodium poly(N -undecanoyl- L -leucylvalinate), was employed at concentrations of 0.25,1.50%,w/v for both MEKC and PEM coatings. Overall, the results revealed partial separation with MEKC and PEM coatings individually. However, MM separation enabled baseline separation of each chiral mixture. The separation of achiral and chiral compounds from different compound classes demonstrates the versatility of this MM approach. [source] Organohalogen contaminants and reproductive hormones in incubating glaucous gulls (Larus hyperboreus) from the Norwegian ArcticENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2006Jonathan Verreault Abstract Organohalogen contaminants detected globally in avian wildlife, including populations from the Arctic, have been related to various reproductive hormone potencies, and altered hormonal balance and functions. Besides legacy organochlorine (OC) substances, that is, polychlorinated biphenyls (PCBs) and OC pesticides and by-products, endocrine-disruptive properties have been defined for chemicals of new and emerging environmental concern, such as polybrominated diphenyl ethers (PBDEs) and metabolically derived products like methylsulfonyl (MeSO2)- and hydroxyl (OH)-PCBs. We investigated the relationships between plasma concentrations of selected legacy OCs, PBDEs, and MeSO2 - and OH-PCB metabolites and the circulating reproductive hormones testosterone (T), 17,-estradiol (E2), and progesterone (P4) in incubating male and female glaucous gulls (Larus hyperboreus) from the Norwegian Arctic. Principal component and regression analyses demonstrated that P4 levels in male glaucous gulls were associated positively with variations of sum (,) PCB, dichloro-diphenyl-trichloroethane (,DDT), chlordane (,CHL), and ,PBDE concentrations, which were the most recalcitrant organohalogens determined in glaucous gulls. No such relationship was found for female glaucous gulls as well as between concentrations of any of the selected organohalogens and levels of T for both sexes. The E2 was not detected in any plasma samples. Present results were highly suggestive that exposure to high organohalogen concentrations in glaucous gulls, particularly the most persistent compound classes, may have the potential to interfere with steroidogenesis and impinge on circulating P4 homeostasis. Because significant effects were found in males exclusively, it cannot be completely ruled out that male glaucous gulls are more sensitive than females to organohalogen-mediated alteration of P4 synthesis and breakdown. [source] Improved automated extraction and separation procedure for soil lipid analysesEUROPEAN JOURNAL OF SOIL SCIENCE, Issue 2 2004G. L. B. Wiesenberg Summary Analysis of soil lipids may contribute to an improved understanding of atmosphere to soil carbon fluxes, soil organic matter source differentiation and pollutant accumulation. Soil lipids, mostly originating from plants and microorganisms, have traditionally been analysed by non-automated extraction and separation methods, which produce several lipid fractions, operationally defined by polarity. Here we present a combination of fast, automated and reproducible techniques, adopted from organic geochemical studies, for preparative separation of individual soil lipid fractions with increasing polarity. These techniques involve commercially available instruments, including accelerated solvent extraction and a two-step automated medium-pressure liquid chromatography procedure. The method yields eight lipid fractions consisting of five fractions fully amenable to gas chromatography/mass spectrometry (GC/MS) (aliphatic hydrocarbons, aromatic hydrocarbons, ketones, alcohols, carboxylic acids), and three fractions of highly polar or high molecular weight compounds (bases, very long-chain wax esters (C40+), high polarity compounds) that were not measurable with GC/MS under standard conditions. We tested the method on five agricultural soils. Results show that (i) mass recoveries for the individual fractions are reproducible, (ii) within individual fractions compound distribution patterns are reproducible, as demonstrated for alkanes and carboxylic acids, and (iii) individual fractions represent distinct and clean compound classes, free of interfering substances detectable by GC/MS. Thus, automated separation can be a fast, effective and reproducible procedure for fractionation of complex mixtures of soil lipids into clean compound classes, directly suitable for a variety of molecular (e.g. GC/MS) and isotopic characterizations (e.g. gas chromatography coupled with isotope ratio monitoring mass spectrometry or accelerator mass spectrometry). [source] Accurate prediction of basicity in aqueous solution with COSMO-RSJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2006Frank Eckert Abstract The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of base pKa constants. For a variety of 43 organic bases the directly calculated values of the free energies of dissociation in water showed a very good correlation with experimental base pKa values (r2 = 0.98), corresponding to a standard deviation of 0.56 pKa units. Thus, we have an a priori prediction method for base pKa with the regression constant and the slope as only adjusted parameters. In accord with recent findings for pKa acidity predictions, the slope of pKa vs. ,Gdiss was significantly smaller than the theoretically expected value of 1/RTln(10). The predictivity of the presented method is general and not restricted to certain compound classes, but systematic corrections of 1 and 2 pKa units for secondary and tertiary aliphatic amines are required, respectively. The pKa prediction method was validated on a set of 58 complex multifunctional drug-like compounds, yielding an RMS accuracy of 0.66 pKa units. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 11,19, 2006 [source] High-throughput determination of the free fraction of drugs strongly bound to plasma proteinsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2004Joachim Schuhmacher Abstract Quantification of protein binding of new chemical entities is an important early screening step during drug discovery and is of fundamental interest for the estimation of safety margins during drug development. In this publication, we describe the development of a new high-throughput assay for the determination of the free drug fraction in plasma (fu). The new technique is an enhancement of the previously published erythrocytes partition method. It is based on the distribution of drugs between plasma water, plasma proteins, and solid-supported lipid membranes (Transil®). The execution of protein binding studies by partitioning is dramatically simplified by substituting erythrocytes with commercially available Transil® beads, and makes the method particularly suitable for high-throughput studies. Eight Bayer compounds from different compound classes covering a wide range of lipophilicities (log P,=,1.9,5.6) and fu values (0.018,35%) were selected for validation of the assay. The results obtained by the new method and by either the erythrocytes partitioning technique or more conventional methods (ultrafiltration and equilibrium dialysis) are identical, confirming that the new method produces valid results even for drugs that are strongly bound to plasma proteins. Precision and accuracy of the data in the cases of very low and high fu values are comparable, indicating that the method is especially suited for highly lipophilic drugs that tend to adsorb to surfaces compared with other methods, like ultrafiltration or equilibrium dialysis, that may produce biased data. The method is also useful for the determination of binding parameters and the pH dependence of fu. In summary, this assay is well suited for high-throughput determination of protein binding during drug discovery and for extended protein binding studies during drug development. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 816,830, 2004 [source] New developments in natural products-based anti-AIDS research,MEDICINAL RESEARCH REVIEWS, Issue 1 2007Donglei Yu Abstract This review discusses anti-HIV natural products from several compound classes, including terpenoids, coumarins, alkaloids, polyphenols, tannins, and flavonoids. Natural products can provide novel anti-AIDS chemotherapeutic leads that are structurally unique or have new mechanisms of action. The drug discovery and development process proceeds from bioactivity-directed isolation and identification of a promising lead natural product, followed by rational design-based structural modification and structure,activity relationship analyses to optimize the lead compound as a drug candidate. This process is notably exemplified by the discovery of the modified betulinic acid derivative, DSB [PA-457], which is currently in Phase II clinical trial and is the first-in-class HIV maturation inhibitor (MI). © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 1, 108,132, 2007 [source] Development of EuroFIR-BASIS , a composition and biological effects database for plant-based bioactive compoundsNUTRITION BULLETIN, Issue 1 2008L. Black Summary Bioactive compounds, such as those derived from plant foods, are of growing interest to the scientific community and food industry because of their putative health-promoting properties. Increasing evidence reports beneficial effects of bioactive compounds, particularly against cancers, cardiovascular diseases and diabetes. EuroFIR-BASIS (BioActive Substances in Food Information System) is a unique online database that collates international research on the composition and biological effects of plant-based bioactive compounds into a single, comprehensive reference resource. EuroFIR-BASIS covers multiple compound classes and 330 major European food plants with data sourced from quality-assessed, peer-reviewed literature. The database is internet-deployed to ensure widespread accessibility and facilitates searches against a number of different variables. EuroFIR-BASIS is intended for use by a wide audience, including scientists, researchers, epidemiologists, food regulatory authorities and product developers in the food industry. The database has been designed to accommodate continual expansion as research develops to ensure that it remains a current and useable resource. [source] NMR and UPLC-qTOF-MS/MS characterisation of novel phenylethanol derivatives of phenylpropanoid glucosides from the leaves of strawberry (Fragaria × ananassa cv. Jonsok)PHYTOCHEMICAL ANALYSIS, Issue 5 2009Kati Hanhineva Abstract Introduction Strawberry (Fragaria × ananassa) is rich in polyphenols, particularly anthocyanins, flavonols, condensed tannins and ellagic tannins. In addition to the fruits, the leaves of strawberry also contain a wide range of phenolic compound classes, but have not been investigated to the same extent as the fruit. Objective To characterise a metabolite group present in the leaves of strawberry, that was not amenable for identification based on earlier information available in the literature. Methodology Methanolic extracts of strawberry leaves were analysed by UPLC-qTOF-MS/MS and iterative quantum mechanical NMR spectral analysis. Results The structures of phenylethanol derivatives of phenylpropanoid glucosides Eutigoside A ( F4) and its two isomeric forms 2-(4-hydroxyphenyl)ethyl-[6- O -(Z)-coumaroyl]- ,- d -glucopyranoside ( F6) and 4-(2-hydroxyethyl)phenyl-[6- O -(e)-coumaroyl]- ,- d -glucopyranoside ( F1) were resolved by NMR and UPLC-qTOF-MS/MS. In addition, two other derivatives of phenylpropanoid glucosides similar to Eutigoside A but possessing different phenolic acid moieties, namely Grayanoside A ( F5) and 2-(4-hydroxyphenyl)ethyl-[6- O -(e)-caffeoyl]- ,- d -glucopyranoside ( F14), were similarly identified. Also, accurate characteristic coupling constants for the subunits are reported and their usefulness in structural analysis is highlighted. Conclusion Chemical analysis of the leaves of strawberry (Fragaria × ananassa cv. Jonsok) resulted in the identification of a compound class, phenylethanol derivatives of phenylpropanoid glycosides, not previously found in strawberry. Copyright © 2009 John Wiley & Sons, Ltd. [source] High-resolution extracted ion chromatography, a new tool for metabolomics and lipidomics using a second-generation orbitrap mass spectrometerRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 10 2009Albert Koulman Most analytical methods in metabolomics are based on one of two strategies. The first strategy is aimed at specifically analysing a limited number of known metabolites or compound classes. Alternatively, an unbiased approach can be used for profiling as many features as possible in a given metabolome without prior knowledge of the identity of these features. Using high-resolution mass spectrometry with instruments capable of measuring m/z ratios with sufficiently low mass measurement uncertainties and simultaneous high scan speeds, it is possible to combine these two strategies, allowing unbiased profiling of biological samples and targeted analysis of specific compounds at the same time without compromises. Such high mass accuracy and mass resolving power reduces the number of candidate metabolites occupying the same retention time and m/z ratio space to a minimum. In this study, we demonstrate how targeted analysis of phospholipids as well as unbiased profiling is achievable using a benchtop orbitrap instrument after high-speed reversed-phase chromatography. The ability to apply both strategies in one experiment is an important step forward in comprehensive analysis of the metabolome. Copyright © 2009 John Wiley & Sons, Ltd. [source] A systems biology investigation of the MEP/terpenoid and shikimate/phenylpropanoid pathways points to multiple levels of metabolic control in sweet basil glandular trichomesTHE PLANT JOURNAL, Issue 3 2008Zhengzhi Xie Summary The glandular trichome is an excellent model system for investigating plant metabolic processes and their regulation within a single cell type. We utilized a proteomics-based approach with isolated trichomes of four different sweet basil (Ocimum basilicum L.) lines possessing very different metabolite profiles to clarify the regulation of metabolism in this single cell type. Significant differences in the distribution and accumulation of the 881 highly abundant and non-redundant protein entries demonstrated that although the proteomes of the glandular trichomes of the four basil lines shared many similarities they were also each quite distinct. Correspondence between proteomic, expressed sequence tag, and metabolic profiling data demonstrated that differential gene expression at major metabolic branch points appears to be responsible for controlling the overall production of phenylpropanoid versus terpenoid constituents in the glandular trichomes of the different basil lines. In contrast, post-transcriptional and post-translational regulation of some enzymes appears to contribute significantly to the chemical diversity observed within compound classes for the different basil lines. Differential phosphorylation of enzymes in the 2- C -methyl- d -erythritol 4-phosphate (MEP)/terpenoid and shikimate/phenylpropanoid pathways appears to play an important role in regulating metabolism in this single cell type. Additionally, precursors for different classes of terpenoids, including mono- and sesquiterpenoids, appear to be almost exclusively supplied by the MEP pathway, and not the mevalonate pathway, in basil glandular trichomes. [source] Arylazoamidoximes and Related Compounds as NO-modulatorsARCHIV DER PHARMAZIE, Issue 1 2010Alexander Schröder Abstract Three amidinoarylhydrazines 1, three arylazoamidines 2, and nine arylazoamidoximes 3 have been synthesized and investigated for their potential to function as nitric oxide (NO) modulators. In-vitro studies demonstrated that 2 and 3 inhibited platelet aggregation (2c, IC50 = 3 ,M) which could also be shown in vivo by inhibition of thrombus formation in arterioles (3a, 22%). Moreover, for all compounds antihypertensive effects were examined in vivo with SHR rats, with 2a being the most potent candidate by lowering blood pressure by 19%. However, no common underlying mechanism of action could be shown. Some of these compounds released HNO non-enzymatically. Incubations with NO synthase isoforms (NOSs) revealed, that compounds 1 to 3 were weak substrates for NOSs but arylazoamidoximes 3 remarkably elevated the NOSs activity in the presence of L -arginine (3h, up to fivefold). In addition, we examined effects on arginase and dimethylarginine dimethylaminohydrolase (DDAH), two further enzymes involved in the complex regulation of NO biosynthesis, to elucidate whether the observed in-vivo effects can be traced back to their modulation. Furthermore, the metabolic fate of arylazoamidoximes 3 was addressed by investigation of a possible N -reductive biotransformation. In summary, novel NO-modulating compound classes are presented, among which arylazoamidoximes 3 are potent activators of NOS isoforms, and arylazoamidines 2 exert in-vivo effects by unknown mechanisms. [source] Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-KetopiperazidesARCHIV DER PHARMAZIE, Issue 12 2004Matthias Gerlach Abstract 1-Phenyl-4-piperazinyl-carbonyl-substituted nitrogen-containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D-24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties. Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization. [source] RelACCS-FP: A Structural Minimalist Approach to Fingerprint DesignCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2008Ye Hu The design and evaluation of structural key-type fingerprints is reported that consist of only 10,30 substructures isolated from randomly generated fragment populations of different classes of active compounds. To identify minimal sets of fragments that carry substantial compound class-specific information, fragment frequency calculations are applied to guide fingerprint generation. These compound class-directed and extremely small structural fingerprints push the design of so-called mini-fingerprints to the limit and are the shortest bit string fingerprints reported to date. For the application of relative frequency-based activity class characteristic substructure fingerprints, a bit density-dependent similarity metric is introduced that makes it possible to adjust similarity coefficients for individual compound classes and balance the recall of active compounds with database selection size. In similarity search trials, these small compound class-directed fingerprints enrich active compounds in relatively small database selection sets and approach or exceed the performance of widely used structural fingerprints of much larger size and higher complexity. [source] In vitro susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis: a European multicenter study during 2000,2001CLINICAL MICROBIOLOGY AND INFECTION, Issue 7 2003M. E. Jones Objective, To assess the current (2001) activity of respiratory fluoroquinolones and comparator agents against respiratory pathogens isolated in European countries. Methods, During 2000,2001, we prospectively collected 1995 isolates of Haemophilus influenzae, 1870 isolates of Streptococcus pneumoniae and 649 isolates of Moraxella catarrhalis from hospital laboratories in France, Germany, Greece, Italy, Spain and the UK. National Committee for Clinical Laboratory Standards (NCCLS)-approved broth microdilution antimicrobial susceptibility testing methods and interpretive criteria were used throughout. Results, Of the S. pneumoniae isolates, 99.6% were susceptible to moxifloxacin, gatifloxacin and levofloxacin; the corresponding figure for H. influenzae was 100%. All M. catarrhalis isolates had moxifloxacin MICs ,,0.12 mg/L. For all three pathogens, fluoroquinolone susceptibility remained unchanged from the previous 1997,98 study. The incidence of penicillin non-susceptibility in the S. pneumoniae isolates tested remained similar to or higher than that recorded in previous studies: France, 165/291 (56.7%); Germany, 46/506 (9.1%); Greece, 20/55 (36.4%); Italy, 45/364 (12.4%); Spain, 146/268 (54.5%); and the UK, 26/386 (6.7%). Significant levels of resistance to oral compounds (cefuroxime, cefaclor, cefdinir, clarithromycin, azithromycin, tetracycline, and trimethoprim,sulfamethoxazole) were detected among S. pneumoniae isolates. ,-Lactamase production among H. influenzae isolates ranged from 6.2% to 33.1% per country, and ampicillin, clarithromycin or trimethoprim,sulfamethoxazole resistance were the most common phenotypes detected. ,-Lactamase production among M. catarrhalis isolates ranged from 94.1% to 100% per country. Conclusions, With the exception of a few localized reports, resistance to moxifloxacin and other new fluoroquinolones in common respiratory pathogens is a rare occurrence, despite significant resistance to other compound classes. Surveillance will play a key role in tracking changes in fluoroquinolone susceptibility in European countries. [source] | ||||||||||||||||