- Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ1) receptor ligands with potent anti-amnesic effect
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The sigma-1 (σ1) receptor plays a significant role in many normal physiological functions and pathological disease states, and as such represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines based on the lead compound 1-[ω-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1a) in which the degree of methylation at the carbon atoms alpha to the piperidine nitrogen was systematically varied. The affinity at σ1 and σ2 receptors and at Δ8-Δ7 sterol isomerase (SI) ranged from subnanomolar to micromolar Ki values. While the highest-affinity was displayed at the σ1, the increase of the degree of methylation in the piperidine ring progressively decreased the affinity. The subnanomolar affinity 1a and 1-[ω-(4-methoxyphenoxy)ethyl]-4-methylpiperidine (1b) displayed potent anti-amnesic effects associated with σ1 receptor agonism, in two memory tests. Automated receptor–small-molecule ligand docking provided a molecular structure-based rationale for the agonistic effects of 1a and 1b. Overall, the class of the phenoxyalkylpiperidines holds potential for the development of high affinity σ1 receptor agonists, and compound 1a, that appears as the best in class (exceeding by far the activity of the reference compound PRE-084) deserves further investigation.
- Abatematteo, Francesca S.,Mosier, Philip D.,Niso, Mauro,Brunetti, Leonardo,Berardi, Francesco,Loiodice, Fulvio,Contino, Marialessandra,Delprat, Benjamin,Maurice, Tangui,Laghezza, Antonio,Abate, Carmen
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- 1,3,4,9-TETRAHYDRO-2H-PYRIDO[3,4-B]INDOLE DERIVATIVE COMPOUNDS AND USES THEREOF
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The present invention relates to 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole derivative compounds and uses thereof. In particular, compounds of the invention have antibacterial activity and/or are capable of re-sensitizing methicillin-resistant Staphylococcus aureus to a P-lactam antibiotic or a combination of a P-lactam antibiotic and a P-lactamase inhibitor. The present invention also relates to a method for producing and using said compounds.
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- Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure
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Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.
- Cheng, Kai,Li, Shiyu,Lv, Xiao,Tian, Yongbin,Kong, Haiyan,Huang, Xufeng,Duan, Yajun,Han, Jihong,Xie, Zhouling,Liao, Chenzhong
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supporting information
p. 1012 - 1018
(2019/02/24)
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- A method for preparing chloro-benzene oxygen carboxylic acid (by machine translation)
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The invention provides a method for preparing carboxylic acid chloro-benzene oxygen, comprising the following steps: S1) phenoxy fatty alcohol in the catalyst B A and under the action of the catalyst, and the chlorinating agent to 2 bit and/or 4 bit selective chlorination reaction, to obtain chloro-benzene oxygen fatty alcohol; said catalyst A is Lewis acid; said catalyst B is C5 - 22 of the thioether, thiazole, isothiazole, thiophene or their halogenated derivatives; S2) [...] fatty alcohol and water, under the action of a catalyst, and an oxidizing agent for the selective catalytic oxidation reaction, get chloro-benzene oxygen carboxylic acid. The invention through the re-design of the process route, the catalyst and the chlorinating agent fine screening, effectively reduces the energy consumption, the selectivity of the dichloride to improve at the same time avoiding the losses of the active ingredient, the resulting chloro-benzene oxygen carboxylic acid content can be up to 98.5% or more, the total yield can be up to 99% or more. (by machine translation)
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Paragraph 0059; 0060
(2019/01/08)
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- TiO2-Supported Re as a General and Chemoselective Heterogeneous Catalyst for Hydrogenation of Carboxylic Acids to Alcohols
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TiO2-supported Re, Re/TiO2, was found to promote selective hydrogenation of carboxylic acids having aromatic and aliphatic moieties to the corresponding alcohols. Re/TiO2showed superior results compared to other transition-metal-loaded TiO2and supported Re catalysts for selective hydrogenation of 3-phenylpropionic acid. 3-phenylpropanol was produced in 97 % yield under mild conditions (5 MPa H2at 140 °C). Contrary to typical heterogeneous catalysts, Re/TiO2does not lead to the formation of dearomatized byproducts. The catalyst is recyclable and shows a wide substrate scope in the synthesis of alcohols (22 examples; up to 97 % isolated yield).
- Toyao, Takashi,Siddiki, S. M. A. Hakim,Touchy, Abeda S.,Onodera, Wataru,Kon, Kenichi,Morita, Yoshitsugu,Kamachi, Takashi,Yoshizawa, Kazunari,Shimizu, Ken-Ichi
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p. 1001 - 1006
(2017/02/05)
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- Aryl ethers of 4-[(2-hydroxyethyl)sulfanyl]pyrimidine derivatives: Pathways of synthesis and fungicidal activity of their salt forms
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2-Amino-4-[(2-aryloxyethyl)sulfanyl]-6-methylpyrimidines were obtained by S-alkylation of 2-amino-6-methylpyrimidin-4(3H)-thione with 2-aryloxyethyl chlorides. Since 2-amino-4-[(2-chloroethyl)sulfanyl]-6-methylpyrimidine is prone to in situ intramolecular cyclization it cannot be used in Claisen reaction. The bromination of the target compounds provided 5-bromo derivatives; some of their hydrochlorides exhibited fungicidal activity.
- Erkin,Klaptyuk,Gurzhii,Yuzikhin,Krutikov
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p. 1274 - 1281
(2016/08/10)
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- Discovery and characterization of nonpeptidyl agonists of the tissue-protective erythropoietin receptors
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Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy. Here, we describe the discovery and characterization of the nonpeptidyl compound STS-E412 (2-[2-(4-chlorophenoxy) ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine), which selectively activates the tissue-protective EPO receptor, comprising an EPO receptor subunit (EPOR) and the common β-chain (CD131). STS-E412 triggered EPO receptor phosphorylation in human neuronal cells. STS-E412 also increased phosphorylation of EPOR, CD131, and the EPO-associated signaling molecules JAK2 and AKT in HEK293 transfectants expressing EPOR and CD131. At low nanomolar concentrations, STS-E412 provided EPO-like cytoprotective effects in primary neuronal cells and renal proximal tubular epithelial cells. The receptor selectivity of STS-E412 was confirmed by a lack of phosphorylation of the EPOR/EPOR homodimer, lack of activity in off-target selectivity screening, and lack of functional effects in erythroleukemia cell line TF-1 and CD34+ progenitor cells. Permeability through artificial membranes and Caco-2 cell monolayers in vitro and penetrance across the blood-brain barrier in vivo suggest potential for central nervous system availability of the compound. To our knowledge, STS-E412 is the first nonpeptidyl, selective activator of the tissue-protective EPOR/CD131 receptor. Further evaluation of the potential of STS-E412 in central nervous system diseases and organ protection is warranted.
- Miller, James L.,Church, Timothy J.,Leonoudakis, Dmitri,Lariosa-Willingham, Karen,Frigon, Normand L.,Tettenborn, Connie S.,Spencer, Jeffrey R.,Punnonen, Juha
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supporting information
p. 357 - 367
(2015/09/01)
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- Copper(ii)-catalyzed C-O coupling of aryl bromides with aliphatic diols: Synthesis of ethers, phenols, and benzo-fused cyclic ethers
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A highly efficient copper-catalyzed C-O cross-coupling reaction between aryl bromides and aliphatic diols has been developed employing a cheaper, more efficient, and easily removable copper(ii) catalyst. A broad range of aryl bromides were coupled with aliphatic diols of different lengths using 5 mol% CuCl2 and 3 equivalents of K2CO3 in the absence of any other ligands or solvents to afford the corresponding hydroxyalkyl aryl ethers in good to excellent yields. In this newly developed protocol, aliphatic diols have multilateral functions as coupling reactants, ligands, and solvents. The resulting hydroxyalkyl aryl ethers were further readily converted into the corresponding phenols, presenting a valuable alternative way to phenols from aryl bromides. Furthermore, it was demonstrated that they are useful intermediates for more advanced molecules such as benzofurans and benzo-fused cyclic ethers. This journal is
- Liu, Yajun,Park, Se Kyung,Xiao, Yan,Chae, Junghyun
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supporting information
p. 4747 - 4753
(2014/06/24)
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- Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold
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Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2- methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel Hsp90 inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated. The structure-activity relationships (SAR) for these compounds was also discussed for further molecular design. This effort afforded the most active inhibitor 13f with improved activity in not only target-based level, but also cell-based level compared with the original hit 1.
- Jia, Jian-Min,Liu, Fang,Xu, Xiao-Li,Guo, Xiao-Ke,Jiang, Fen,Cherfaoui, Bahidja,Sun, Hao-Peng,You, Qi-Dong
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supporting information
p. 1557 - 1561
(2014/03/21)
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- SUBSTITUTED TRIAZOLO-PYRIMIDINE COMPOUNDS FOR MODULATING CELL PROLIFERATION, DIFFERENTIATION AND SURVIVAL
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Disclosed herein are erythropoietin-mimetic compounds of Formula I, which modulate the survival, function, or differentiation of, for example, kidney cells, neurons, erythroid cells, or other erythropoietin-responsive cells. The present invention also relates to compounds and methods that preferentially modulate cells expressing the tissue-protective erythropoietin receptor. The compounds of the invention are useful in preventing and treating diseases, such as anemia, organ injury, and diseases of the central nervous system, and as an adjunct to cellular treatments, such as stem cell therapies.
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Paragraph 0574; 0575
(2014/05/25)
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- Copper(II) triflate-catalyzed reduction of carboxylic acids to alcohols and reductive etherification of carbonyl compounds
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A protocol is described for the reduction of carboxylic acids to primary alcohols using 1,1,3,3-tetramethyldisiloxane (TMDS) and a catalytic amount of Cu(OTf)2. Aliphatic as well as aromatic carboxylic acids are reduced in high selectivity and good yields. TMDS/Cu(OTf)2 has also been found to be an efficient catalytic reducing system for the preparation of symmetrical ethers from carbonyl compounds under mild conditions.
- Zhang, Yin-Jie,Dayoub, Wissam,Chen, Guo-Rong,Lemaire, Marc
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experimental part
p. 7400 - 7407
(2012/09/10)
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- The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues
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Previous studies have documented that substituted 8-oxycaffeines act as inhibitors of human monoamine oxidase (MAO) B. A particularly potent inhibitor among the reported compounds was 8-(2-phenoxyethoxy)caffeine with an IC 50 value of 0.383M towards MAO-B. In an attempt to improve on the inhibition potency of this compound and to discover highly potent reversible MAO-B inhibitors, in the present study, a series of 8-(2-phenoxyethoxy)caffeine analogues containing various substituents on C4 of the phenoxy ring, were synthesized and evaluated as inhibitors of human MAO-A and -B. The results show that the 8-(2-phenoxyethoxy)caffeine analogues are selective and reversible MAO-B inhibitors with the most potent homologue, 8-{2-[4-(trifluoromethyl) phenoxy]ethoxy}caffeine, exhibiting an IC50 value of 0.061μM. These highly potent inhibitors are useful leads in the design of therapies for neurodegenerative disorders such as Parkinsons disease. Georg Thieme Verlag KG Stuttgart New York.
- Strydom,Bergh,Petzer
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p. 513 - 518
(2013/01/15)
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- Substituted piperazines and diazepanes
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A novel class of substituted piperazines and diazepanes, pharmaceutical compositions comprising them and use thereof in the treatment of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.
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Page/Page column 93
(2010/02/05)
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- Synthesis of analogs of juvenile hormons proceeding from phenol derivatives
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New potential juvenoids, esters of alkenoic and alkadienoic acids with phenoxy-and phenoxy-phenoxyethanol were synthesized, and also esters of phenoxyacetic acid with alkenols amd alkadienols.
- Yamansarova,Kukovinets,Kukovinets,Zainullin,Galin,Kunakova,Zorin,Tolstikov
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p. 246 - 255
(2007/10/03)
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- Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
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As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts.
- Szajnman, Sergio H.,Yan, Wen,Bailey, Brian N.,Docampo, Roberto,Elhalem, Eleonora,Rodriguez, Juan B.
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p. 1826 - 1840
(2007/10/03)
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- Fungicidal 2-aryl-2-cyano-2-(aryloxyalkyl)ethyl-1,2-4-triazoles
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2-aryl-2-cyano-2-(aryloxyalkyl)ethyl-1,2,4-triazoles of the formula STR1 wherein Ar1 and Ar2 are optionally substituted aryl groups which may or may not be different, R is hydrogen or alkyl, n is an integer of at least one, and the agronomically acceptable enantiomorphs, acid addition salts and metal salt complexes thereof, compositions containing these compounds and their uses as fungicides, particularly against phytopathogenic fungi.
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- Structure-activity studies of 3-benzoylpropionic acid derivatives suppressing adjuvant arthritis
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3-Benzoylpropionic acid derivatives possess an immunomodulative activity and suppress adjuvant arthritis. To understand how substituents affect the biological activity, the quantitative structure-activity relationships of 30 compounds were analyzed by the adaptive least-squares method. For the suppressing activity in rats, the electronic effects and the structural feature of the substituent on benzene ring were suggested to be important. To reinforce and confirm the correlation, 4 additional compounds of phenoxybutyric acid derivatives were synthesized and tested with the rat adjuvant-induced arthritis. These compounds were found to have potent suppressing activity.
- Kawashima,Kameo,Kato,Hasegawa,Tomisawa,Hatayama,Hirono,Moriguchi
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p. 774 - 777
(2007/10/02)
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