- Development and preclinical evaluation of new inhaled lipoglycopeptides for the treatment of persistent pulmonary methicillin-resistant staphylococcus aureus infections
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Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.
- Plaunt, Adam J.,Rose, Sasha J.,Kang, Jeong Yeon,Chen, Kuan-Ju,LaSala, Daniel,Heckler, Ryan P.,Dorfman, Arielle,Smith, Barrett T.,Chun, Donald,Viramontes, Veronica,Macaluso, Antonio,Li, Zhili,Zhou, Yuchen,Mark, Lilly,Basso, Jessica,Leifer, Franziska G.,Corboz, Michel R.,Chapman, Richard W.,Cipolla, David,Perkins, Walter R.,Malinin, Vladimir S.,Konicek, Donna M.
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supporting information
(2021/06/22)
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- LIPO-GLYCOPEPTIDE CLEAVABLE DERIVATIVES AND USES THEREOF
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The present invention provides certain lipo-glycopeptide cleavable derivatives and methods for using the same for the treatment of bacterial infections, for example, pulmonary bacterial infections. The LGPC derivatives include a cleavable moiety that in certain embodiments, is designed to allow for cellular uptake and/or a more rapid clearance of the glycopeptide metabolite (i.e., the cleaved glycopeptide) from the site of administration (e.g., the lung) as compared to the uncleaved LGPC. The bacterial infection can comprise intracellular bacteria, planktonic bacteria, bacteria present in a biofilm, or a combination thereof.
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Paragraph 237
(2020/06/10)
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- Synthesis of: N-acyl amide natural products using a versatile adenylating biocatalyst
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Natural products are secondary metabolites produced by many different organisms such as bacteria, fungi and plants. These biologically active molecules have been widely exploited for clinical application. Here we investigate TamA, a key enzyme from the biosynthetic pathway of tambjamine YP1, an acylated bipyrrole that is produced by the marine microorganism Pseudoalteromonas tunicata. TamA is a didomain enzyme composed of a catalytic adenylation (ANL) and an acyl carrier protein (ACP) domain that together control the fatty acid chain length of the YP1. Here we show that the TamA ANL domain alone can be used to generate a range of acyl adenylates that can be captured by a number of amines thus leading to the production of a series of fatty N-acyl amides. We exploit this biocatalytic promiscuity to produce the recently discovered class of N-acyl histidine amide natural products from Legionella pneumophila.
- Marchetti, Piera M.,Richardson, Shona M.,Kariem, Noor M.,Campopiano, Dominic J.
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supporting information
p. 1192 - 1196
(2019/07/31)
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- A catalyst-free, waste-less ethanol-based solvothermal synthesis of amides
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A green, one-pot approach based on the solvothermal amidation of carboxylic acids with amines has been developed for the synthesis of diverse aliphatic and aromatic amides. It does not require the use of catalysts or coupling reagents and it occurs in the presence of ethanol that has been proved to have a key role in the process. The proposed strategy is also extendable to biologically active amides and could represent a low-cost and waste-less alternative to the common synthetic pathways.
- Dalu, Francesca,Scorciapino, Mariano A.,Cara, Claudio,Luridiana, Alberto,Musinu, Anna,Casu, Mariano,Secci, Francesco,Cannas, Carla
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supporting information
p. 375 - 381
(2018/02/07)
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- Design, synthesis and CoMFA studies of OEA derivatives as FAAH inhibitors
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A total of 26 novel oleoylethanolamide derivatives were designed, synthesized, and characterized. All synthesized targets compounds were screened for their inhibitory activities against fatty acid amide hydrolase. Among of them, 13 compounds inhibit fatty acid amide hydrolase by 50% at the concentration of 100 μM. Of these compounds, the most active one is compound 9, which inhibit fatty acid amide hydrolase activity 98.35% at the concentration of 100 μM. Comparative molecular field analysis analyzes were performed based on obtained biological activities data and resulted in a statistically reliable comparative molecular field analysis model with high predictive abilities (r2 = 0.978, q2 = 0.613).
- Han, Daxiong,Wang, Biyan,Jin, Hui,Wang, Haiyan,Chen, Meimei
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p. 2951 - 2966
(2017/10/06)
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- IMPROVED PROCESS FOR ALAKNOLAMIDE SYNTHESIS
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The present invention is directed to a process of making alkanolamides wherein the "aging" time is reduced and the diethanol amide to ester ratio in the finished product is increased. Further provided is an additive composition comprising an alkanolamide which contains a reduced amount of DEA and BHEP.
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Page/Page column 25
(2016/03/22)
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- Fatty acid monoethanol amide succinate sulfonate and its preparation method and application
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The invention provides a preparation method for fatty acid monoethanolamide succinate sulfonate. The preparation method is characterized by comprising the steps of generating amidation reaction by fatty acid and monoethanolamide to generate fatty acid monoethanolamide which is reacted with butenedioic acid or maleic anhydride to generate fatty acid monoethanolamide butenedioic acid ester, and generating salt formation reaction of the fatty acid monoethanolamide butenedioic acid ester and hydrosulphite to generate the fatty acid monoethanolamide succinate sulfonate. Compared with the prior art, trace cutting liquid prepared from the fatty acid monoethanolamide succinate sulfonate provided by the invention has high lubricating property, extreme pressure antiwear property and biological degradability; a high-end requirement on metal processing can be met only by using an extremely small amount of the trace cutting liquid; therefore, harm to the environment and workers is alleviated, and the pollution to the environment is reduced to the maximum extent.
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Paragraph 0067
(2016/11/24)
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- Pharmaceuticals and Surfactants from Alga-Derived Feedstock: Amidation of Fatty Acids and Their Derivatives with Amino Alcohols
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Amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, was demonstrated with zeolites and mesoporous materials as catalysts and ethanolamine, alaninol, and leucinol. The last two can be derived from amino acids present in alga. The main products were fatty alkanol amides and the corresponding ester amines, as confirmed by NMR and IR spectroscopy. Thermal amidation of technical-grade oleic acid and stearic acid at 180°C with ethanolamine were non-negligible; both gave 61% conversion. In the amidation of stearic acid with ethanolamine, the conversion over H-Beta-150 was 80% after 3 h, whereas only 63% conversion was achieved for oleic acid; this shows that a microporous catalyst is not suitable for this acid and exhibits a wrinkled conformation. The highest selectivity to stearoyl ethanolamide of 92% was achieved with mildly acidic H-MCM-41 at 70% conversion in 3 h at 180°C. Highly acidic catalysts favored the formation of the ester amine, whereas the amide was obtained with a catalyst that exhibited an optimum acidity. The conversion levels achieved with different fatty acids in the range C12-C18 were similar; this shows that the fatty acid length does not affect the amidation rate. The amidation of methyl palmitate and biodiesel gave low conversions over an acidic catalyst, which suggested that the reaction mechanism in the amidation of esters was different. Pores versus acidity: The structures and properties of zeolites and mesoporous materials are investigated as catalysts for the amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, with ethanolamine, alaninol, and leucinol as nitrogen sources.
- Tkacheva, Anastasia,Dosmagambetova, Inkar,Chapellier, Yann,M?ki-Arvela, P?ivi,Hachemi, Imane,Savela, Risto,Leino, Reko,Viegas, Carolina,Kumar, Narendra,Er?nen, Kari,Hemming, Jarl,Smeds, Annika,Murzin, Dmitry Yu.
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p. 2670 - 2680
(2015/09/02)
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- Alkyl sulfonyl derivatized PAMAM-G2 dendrimers as nonviral gene delivery vectors with improved transfection efficiencies
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Amphiphilic dendrimer-based gene delivery vectors bearing peripheral alkyl sulfonyl hydrophobic tails were constructed using low-generation PAMAM-G2 as the core and functionalized by means of the aza-Michael type addition of its primary amino groups to vinylsulfone derivatives as an efficient tool for surface engineering. While the unmodified PAMAM-G2 was unable to efficiently transfect eukaryotic cells, functionalized PAMAM-G2 dendrimers were able to bind DNA at low N/P ratios, protect DNA from digestion with DNase I and showed high transfection efficiencies and low cytotoxicity. Dendrimers with a C18 alkyl chain produced transfection efficiencies up to 3.1 fold higher than LipofectAMINE 2000 in CHO-k1 cells. The dendriplexes based in functionalized PAMAM-G2 also showed the ability to retain their transfection properties in the presence of serum and the ability to transfect different eukaryotic cell lines such as Neuro-2A and RAW 264.7. Taking advantage of the vinylsulfone chemistry, fluorescent PAMAM-G2 derivatives of these vectors were prepared as molecular probes to determine cellular uptake and internalization through a clathrin-independent mechanism.
- Morales-Sanfrutos, Julia,Megia-Fernandez, Alicia,Hernandez-Mateo, Fernando,Giron-Gonzalez, Ma Dolores,Salto-Gonzalez, Rafael,Santoyo-Gonzalez, Francisco
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experimental part
p. 851 - 864
(2011/03/22)
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- Synthesis and biological activity of N-acyl O-indolylalkyl ethanolamines
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The plant-growth regulators, indole-3-carboxylic acids, were introduced into N-acyl ethanolamines, and a series of N-acyl O-indolylalkyl ethanolamines were prepared. Their biological activities to regulate rape hypocotyl elongation, cucumber cotyledon expansion and common wheat coleoptile growth were tested. The results indicate that the title compounds inhibited rape hypocotyl elongation, especially the indole-3-propionic acid derivatives, whose bioactivity was better than that of indole-3-acetic acid.
- Jiang, Shaoliang,Gao, Jianrong,Han, Liang
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experimental part
p. 768 - 770
(2011/11/13)
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- Method For Producing Fatty Acid Alkanol Amides
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The invention relates to a method for producing fatty acid alkanol amides by reacting at least one amine that contains at least one primary or secondary amino group and at least one hydroxyl group with at least one fatty acid to form an ammonium salt, said ammonium salt being subsequently converted into the alkanol amide by means of microwave radiation.
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Page/Page column 7
(2010/02/17)
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- Synthesis and anticonvulsant activity of N-(2-hydroxyethyl)amide derivatives
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A series novel of N-(2-hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N-(2-hydroxyethyl)decanamide 1g, N-(2-hydroxyethyl)palmitamide 1l, and N-(2-hydroxyeth-yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti-epileptic drug valproate. In the anti-MES potency test, these compounds exhibited median effective doses (ED50) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD50) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti-epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g, 1l, and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3-mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.
- Guan, Li-Ping,Zhao, Dong-Hai,Xiu, Jing-Hui,Sui, Xin,Piao, Hu-Ri,Quan, Zhe-Shan
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experimental part
p. 34 - 40
(2009/06/18)
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- Synthesis of neoglycolipids based on D-lactose
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A synthesis was performed of amphiphilic D-lactose derivatives differing by the length and number of aliphatic chains. The compounds may be applied to the carbohydrate modification of phosphatidylcholine liposomes.
- Gur'eva,Budanova,Sebyakin
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experimental part
p. 173 - 177
(2009/09/06)
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- N-acylation of ethanolamine using lipase: A chemoselective catalyst
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The N-acylation of ethanolamine (2) with various fatty acids 1a-d and esters of fatty acids 1e-h using Candida antarctica B lipase (Novozym 435) are described and optimum conditions for selective N-acylation rather than O-acylation are also discussed. Microwave assisted solution phase, solid supported and conventional methods were investigated and results were compared. There is a synergy between the enzyme catalysis and microwave irradiation.
- Kidwai, Mazaahir,Poddar, Roona,Mothsra, Poonam
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experimental part
(2010/04/22)
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- Synthesis of new plant growth regulator: N-(Fatty acid) O-aryloxyacetyl ethanolamine
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N-(Fatty acyl) O-aryloxyacetyl ethanolamines, prepared from N-acylethanolamine (NAE) and aryloxyacetic acid, were tested for plant growth regulating activity. Compared with N-stearoylethanolamine, most compounds exhibit improved plant growth stimulating activity. In particular, those with chlorine on aryl ring show better activity than 2,4-dichlorophenyloxyacetic acid in stimulating hypocotyls elongation of rape which indicates that chlorine on aryl ring appears significant. Moreover, these derivatives display improved solubility.
- Han, Liang,Gao, Jian-Rong,Li, Zheng-Ming,Zhang, Yun,Guo, Wei-Ming
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p. 3231 - 3234
(2008/02/07)
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- USE OF CERTAIN N-ACYLETHANOLAMINES TO ACHIEVE ETHYLENE- AND CYTOKININ-LIKE EFFECTS IN PLANTS AND FUNGI
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N-acylethanolamines (NAEs) that can deliver an ethylene- or cytokinin-like effects to a plant, plant part or fungus are disclosed. Also disclosed are methods of using the NAES.
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- Process for the production of 2-alkyl- or alkenyl-2-oxazolines
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A process for the production of 2-alkyl- or alkenyl-2-oxazolines, in which the alkyl or alkenyl group may be a hydroxy-, dihydroxy- or hydroxy, C1 -C2 -alkoxy-substituted hydrocarbon radical containing at least 7 carbon atoms, produces the subject compounds in high yields when C8 -C22 fatty acids or esters thereof are reacted with 2-amino-ethanol or ethanolamides of these fatty acids in the presence of titanium or zirconium compounds corresponding to the formula M(OR2)4 wherein M=Ti or Zr.
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- Phenolic esteramide antioxidants
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Novel phenolically substituted esterbisamides as antioxidants useful for the protection of organic materials such as synthetic and natural rubbers, plastics and petroleum products against oxidative degradation.
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