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951.
952.
Timothy M. Chapman Simon A. Osborne Nathalie Bouloc Jonathan M. Large Claire Wallace Kristian Birchall Keith H. Ansell Hayley M. Jones Debra Taylor Barbara Clough Judith L. Green Anthony A. Holder 《Bioorganic & medicinal chemistry letters》2013,23(10):3064-3069
A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria. 相似文献
953.
Takaaki Kubota Yuichiro Ishiguro Azusa Takahashi-Nakaguchi Jane Fromont Tohru Gonoi Jun’ichi Kobayashi 《Bioorganic & medicinal chemistry letters》2013,23(1):244-247
Three new polyketides, manzamenones L–N (1–3), have been isolated from an Okinawan marine sponge of the genus Plakortis. The structures of 1–3 were elucidated on the basis of spectroscopic data. Manzamenones L–N (1–3) were new dimeric fatty-acid derivatives consisting of a tetrahydroindenone with three carboxy groups and two hexadecanyl chains. Manzamenones M (2) and N (3) showed antimicrobial activity against several bacteria and fungi. 相似文献
954.
Sajiv K. Nair Jean J. Matthews Stephan J. Cripps Hengmiao Cheng Jacqui E. Hoffman Christopher Smith Stanley Kupchinsky Michael Siu Wendy D. Taylor Yong Wang Theodore O. Johnson Klaus R. Dress Martin P. Edwards Sue Zhou Natilie A. Hosea Amy LaPaglia Ping Kang Arturo Castro Deepak Dalvie 《Bioorganic & medicinal chemistry letters》2013,23(8):2344-2348
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure–activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay. 相似文献
955.
In nitrogen (N) fixing symbioses, host‐symbiont specificity, genetic variation in bacterial symbionts and environmental variation represent fundamental constraints on the ecology, evolution and practical uses of these interactions, but detailed information is lacking for many naturally occurring N‐fixers. This study examined phylogenetic host specificity of Frankia in field‐collected nodules of two Alnus species (A. tenuifolia and A. viridis) in interior Alaska and, for A. tenuifolia, distribution, diversity, spatial autocorrelation and correlation with specific soil factors of Frankia genotypes in nodules collected from replicated habitats representing endpoints of a primary sere. Frankia genotypes most commonly associated with each host belonged to different clades within the Alnus‐infective Frankia clade, and for A. tenuifolia, were divergent from previously described Frankia. A. tenuifolia nodules from early and late succession habitats harboured distinct Frankia assemblages. In early succession, a single genotype inhabited 71% of nodules with no discernable autocorrelation at any scale, while late succession Frankia were more diverse, differed widely among plants within a site and were significantly autocorrelated within and among plants. Early succession Frankia genotype occurrence was strongly correlated with carbon/nitrogen ratio in the mineral soil fraction, while in late succession, the most common genotypes were correlated with different soil variables. Our results suggest that phylogenetic specificity is a significant factor in the A. tenuifolia‐Frankia interaction and that significant habitat‐based differentiation may exist among A. tenuifolia‐infective genotypes. This is consistent with our hypothesis that A. tenuifolia selects specific Frankia genotypes from early succession soils and that this choice is attenuated in late succession. 相似文献
956.
Umashankar Das Ravi S.P. Singh Jane Alcorn Mark R. Hickman Richard J. Sciotti Susan E. Leed Patricia J. Lee Norma Roncal Jonathan R. Dimmock 《Bioorganic & medicinal chemistry》2013,21(23):7250-7256
Drug resistance is a major challenge in antimalarial chemotherapy. In addition, a complete cure of malaria requires intervention at various stages in the development of the parasite within the host. There are only a few antimalarials that target the liver stage of the Plasmodium species which is an essential part of the life cycle of the malarial parasite. We report a series of antimalarial 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs 1–5, a number of which exhibit potent in vitro growth-inhibiting properties towards drug-sensitive D6 and drug-resistant C235 strains of Plasmodium falciparum as well as inhibiting the liver stage development of the malarial life cycle. The compounds 2b (IC50: 165 ng/mL), 3b (IC50: 186 ng/mL), 5c (IC50: 159 ng/mL) and 5d (IC50: 93.5 ng/mL) emerged as lead molecules that inhibit liver stage Plasmodium berghei and are significantly more potent than chloroquine (IC50: >2000 ng/mL) and mefloquine (IC50: >2000 ng/mL) in this screen. All the compounds that showed potent inhibitory activity against the P. berghei liver stage were nontoxic to human HepG2 liver cells (IC50: >2000 ng/mL). The compounds 5a and 5b exhibit comparable metabolic stability as chloroquine and mefloquine in human plasma and the most potent compound 5d demonstrated suitable permeability characteristics using the MDCK monolayer. These results emphasize the value of 3,5-bis(benzylidene)-4-piperidones as novel antimalarials for further drug development. 相似文献
957.
Suresh K. Mohankumar Carla G. Taylor Linda Siemens Peter Zahradka 《The Journal of nutritional biochemistry》2013,24(2):445-456
Conjugated linoleic acid (CLA), a dietary lipid, has been proposed as an antidiabetic agent. However, studies specifically addressing the molecular dynamics of CLA on skeletal muscle glucose transport and differences between the key isomers are limited. We demonstrate that acute exposure of L6 myotubes to cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12) CLA isomers mimics insulin action by stimulating glucose uptake and glucose transporter-4 (GLUT4) trafficking. Both c9,t10-CLA and t10,c12-CLA stimulate the phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase) p85 subunit and Akt substrate-160 kDa (AS160), while showing isomer-specific effects on AMP-activated protein kinase (AMPK). CLA isomers showed synergistic effects with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). Blocking PI3-kinase and AMPK prevented the stimulatory effects of t10,c12-CLA on AS160 phosphorylation and glucose uptake, indicating that this isomer acts via a PI3-kinase and AMPK-dependent mechanism, whereas the mechanism of c9,t11-CLA remains unclear. Intriguingly, CLA isomers sensitized insulin-Akt-responsive glucose uptake and prevented high insulin-induced Akt desensitisation. Together, these results establish that CLA exhibits isomer-specific effects on GLUT4 trafficking and the increase in glucose uptake induced by CLA treatment of L6 myotubes occurs via pathways that are distinctive from those utilised by insulin. 相似文献
958.
Ravjit K. Khangura Gordon C. MacNish William J. MacLeod Vivien A. Vanstone Colin D. Hanbury Robert Loughman Jane E. Speijers 《Journal of Phytopathology》2013,161(11-12):828-840
Two separate surveys of root diseases of cereals in the Western Australian (WA) cereal belt were conducted: the first conducted annually for wheat and barley during 1976–1982 and the second for wheat during 2005–2007. For the 1976–1982 survey, the cereal belt was divided into 15 zones based on the location and rainfall. Sampling was representative of the actual cropping area, with both wheat and barley sampling sites selected by zone as a percentage of total sites. Over 31 000 plants were assessed from a total of 996 fields. Average take‐all incidence ranged from 3% in the northern low rainfall zone to 57% in the southern high rainfall zone. Other root diseases assessed included rhizoctonia root rot, fusarium crown rot and subcrown internode discolouration. During the 2005–2007 survey, around 20 000 plants from a total of 210 fields being intensively cropped with cereals were surveyed for take‐all, rhizoctonia root rot, fusarium crown rot, common root rot, root lesion nematode and cereal cyst nematode. The 2005–2007 survey results indicated that root and crown diseases prevailed in paddocks frequently cropped with cereals and occurred at damaging levels across all WA cropping districts surveyed. The more recent root disease survey identified that the fungal diseases rhizoctonia root rot and fusarium crown rot and the root lesion nematode were the most serious impediments to intensive cereal production, particularly in the southern region of WA. Comparing the 2005–2007 results with the previous survey of 1976–1982, the relative importance of take‐all appears to have declined over the past 30 years. 相似文献
959.
Christin Liptow Anne-Marie Tillman Matty Janssen Ola Wallberg Glenn A. Taylor 《The International Journal of Life Cycle Assessment》2013,18(5):1071-1081
Purpose
In order to reduce its environmental impact, the chemical industry no longer produces base chemicals such as ethylene, solely from fossil, but also from biomass-based feedstocks. However, a biomass option suitable for one region might not be as suitable for another region due to, e.g., long transport and the related environmental. Therefore, local biomass alternatives and the environmental impact related to the production of chemicals from these alternatives need to be investigated. This study assesses the environmental impact of producing ethylene from Swedish wood ethanol.Methods
The study was conducted following the methodology of life cycle assessment. The life cycle was assessed using a cradle-to-gate perspective for the production of 50,000 tonnes ethylene/year for the impact categories global warming, acidification (ACP), photochemical ozone creation, and eutrophication (EP).Results and discussion
The production of enzymes used during the life cycle had a significant effect on all investigated impacts. However, reduced consumption of enzyme product, which could possibly be realized considering the rapid development of enzymes, lowered the overall environmental impact of the ethylene. Another approach could be to use alternative hydrolyzing agents. However, little information on their environmental impact is available. An additional key contributor, with regard to ACP, EP, and POCP, was the ethanol production. Therefore, further improvements with regard to the process’ design may have beneficial effects on its environmental impact.Conclusions
The study assessed the environmental impact of wood ethylene and pointed to several directions for improvements, such as improved enzyme production and reduced consumption of enzyme products. Moreover, the analysis showed that further investigations into other process options and increase of ethylene production from biomass are worth continued research. 相似文献960.
Bloodstream‐form Trypanosoma brucei acquire iron by receptor‐mediated endocytosis of host transferrin. However, the mechanism(s) by which iron is then transferred from the lysosome to the cytosol are unresolved. Here, we provide evidence for the involvement of a protein (TbMLP) orthologous to the mammalian endolysosomal cation channel Mucolipin 1. In T. brucei, we show that this protein is localized to the single parasite lysosome. TbMLP null mutants could only be generated in the presence of an expressed ectopic copy, suggesting that the protein is essential. RNAi‐mediated ablation resulted in a growth defect in vitro and led to a sevenfold increase in susceptibility to the iron‐chelators deferoxamine and salicylhydroxamic acid. Conditional null mutants remained viable when the ectopic copy was repressed, but were hypersensitive to deferoxamine and displayed a growth defect similar to that observed following RNAi. The conditional nulls also retained virulence in vivo in the absence of the doxycycline inducer. These data provide strong evidence that TbMLP has a role in import of iron into the cytosol of African trypanosomes. They also indicate that even when expression is greatly reduced, there is sufficient protein, or an alternative mechanism, to provide the parasite with an adequate supply of cytosolic iron. 相似文献