- Hit-to-lead optimization of novel benzimidazole phenylacetamides as broad spectrum trypanosomacides
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Trypanosoma cruzi and Trypanosoma brucei are the parasitic causative agents of Chagas disease and human African trypanosomiasis (HAT), respectively. The drugs currently used to treat these diseases are not efficacious against all stages and/or parasite sub-species, often displaying side effects. Herein, we report the SAR exploration of a novel hit, 2-(4-chlorophenyl)-N-(1-propyl-1H-benzimidazol-2-yl)acetamide previously identified from high throughput screens against T. cruzi, Trypanosoma brucei brucei and Leishmania donovani. An informative set of analogues was synthesized incorporating key modifications of the scaffold resulting in improved potency whilst the majority of compounds retained low cytotoxicity against H9c2 and HEK293 cell lines. The SAR observed against T. cruzi broadly matches that observed against T.b. brucei, suggesting the possibility for a broad-spectrum candidate. This class of compounds therefore warrants further investigation towards development as a treatment for Chagas disease and HAT. This journal is
- Avery, Vicky M.,Baell, Jonathan,McNamara, Nicole,Rahmani, Raphael,Sykes, Melissa L.
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supporting information
p. 685 - 695
(2020/08/24)
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- A Simple Method for the Preparation of Stainless and Highly Pure Trichloroacetimidates
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We describe a method for obtaining various allylic, benzylic, and glucosyl 2,2,2-trichloroacetimidates (TCAIs) as stainless liquids or solids at the crude stage. The general synthetic method for the preparation of TCAIs often leads to stained products, and further purification of crude TCAIs causes decomposition due to their instability. In the described method, we use a solvent that barely dissolves the reactant, providing stainless and sufficiently pure TCAIs without requiring a purification step. Furthermore, the reaction mixture is turbid at the beginning and clear at the end, allowing us to monitor the progress of the reaction visually.
- Ikeuchi, Kazutada,Murasawa, Kentaro,Yamada, Hidetoshi
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supporting information
p. 1308 - 1312
(2019/06/20)
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- Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction
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Abstract: We utilized the indium-mediated allylation reaction for the synthesis of carbohydrate structures containing the 3-deoxy-2-ulose motif, a barely investigated compound class. The stereoselective outcome can be controlled by the presence or absence of a chelating group in α-position to the carbonyl function. By introduction of an UV-active allyl building block, we enabled epimer separation by HPLC towards the synthesis of 3-deoxy-d-glycero-d-galacto-2-nonulose, the carboxyl-reduced analogue of widely distributed 3-deoxy-d-glycero-d-galacto-nonulosonic acid (Kdn). Ozonolysis of the introduced 2-C-methylidenepropan-1-ol motif provided the desired 3-deoxy-2-uloses. Graphical abstract: [Figure not available: see fulltext.].
- Gintner, Manuel,Denner, Christian,Schm?lzer, Christoph,Fischer, Michael,Frühauf, Peter,K?hlig, Hanspeter,Schmid, Walther
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- New mannose derivatives: The tetrazole analogue of mannose-6-phosphate as angiogenesis inhibitor
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Two novel compounds with mannose-derived structure, bearing a tetrazole (compound 3) and a sulfone group (compound 4) in terminal position, have been prepared from methyl α-d-mannopyranoside in reduced number of steps. The angiogenic activity of 3 and 4 has been screened using the chick chorioallantoic membrane (CAM) method. Tetrazole 3 has been identified to possess a promising bioactivity, being identified as angiogenesis inhibitor, with 68% of neovascular vessels when compared to control (PBS).
- Ionescu, C?t?lina,Sippelli, Simona,Toupet, Lo?c,Barragan-Montero, Véronique
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supporting information
p. 636 - 639
(2016/01/09)
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- Br?nsted acid catalyzed monoalkylation of anilines with trichloroacetimidates
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Trichloroacetimidates are useful alkylating agents for aromatic amines, requiring only a catalytic amount of a Br?nsted acid to facilitate the reaction. Monoalkylation predominates under these conditions. Electron-poor anilines provide superior yields, with electron-rich anilines sometimes showing competitive Friedel-Crafts alkylation. A single flask protocol with formation of the imidate in situ is demonstrated, providing a convenient method for the direct substitution of alcohols with anilines. Reaction with a chiral imidate favors a mechanism that proceeds through a carbocation intermediate.
- Wallach, Daniel R.,Stege, Patrick C.,Shah, Jigisha P.,Chisholm, John D.
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p. 1993 - 2000
(2015/02/19)
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- Alkylation of thiols with trichloroacetimidates under neutral conditions
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Trichloroacetimidates are displaced with thiols to form the corresponding sulfides without the need for an added acid or base by simply heating the reactants in refluxing THF. This operationally simple procedure provides the corresponding sulfides in excellent yields with only the formation of the neutral trichloroacetamide as the side product. The imidate may also be formed in situ, allowing for a direct method for the formation of sulfides from alcohols. This reaction provides a general method for the synthesis of a variety of sulfides from inexpensive and readily available alcohol starting materials.
- Duffy, Brian C.,Howard, Kyle T.,Chisholm, John D.
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supporting information
p. 3301 - 3305
(2015/03/04)
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- A novel copper-catalyzed synthesis of functionalized alkynyl imidates and alkynyl thioimidates
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A copper-catalyzed one-pot synthesis of alkynyl imidates and alkynyl thioimidates via coupling reactions of terminal alkynes with trichloroimidates, generated in situ from trichloroacetonitrile and benzyl alcohols or thiols, is reported.
- Yavari, Issa,Nematpour, Manijeh
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p. 4973 - 4974
(2013/09/02)
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- Gold(I)-catalyzed arylmethylation of terminal alkynes
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AuCl/AgOTf catalyzes the reaction of terminal alkynes with aryl trichloroacetimidate to afford arylmethylation products in moderate to good yields.
- Li, Changkun,Li, Weibin,Wang, Jianbo
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supporting information; experimental part
p. 2533 - 2535
(2009/07/26)
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- Gas-phase fragmentation of γ-lactone derivatives by electrospray ionization tandem mass spectrometry
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Fragmentation reactions of β-hydroxymethyl-, β-acetoxymethyl- and β-benzyloxymethyl-butenolides and the corresponding γ-butyrolactones were investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS) using collision-induced dissociation (CID). This study revealed that loss of H2O [M+H-18]+ is the main fragmentation process for β-hydroxymethylbutenolide (1) and β-hydroxymethyl-γ- butyrolactone (2). Loss of ketene ([M+H-42]+) is the major fragmentation process for protonated β-acetoxymethyl-γ-butyrolactone (4), but not for β-acetoxymethylbutenolide (3). The benzyl cation (m/z 91) is the major ion in the ESI-MS/MS spectra of β-benzyloxymethylbutenolide (5) and β-benzyloxymethyl-γ-butyrolactone (6). The different side chain at the β-position and the double bond presence afforded some product ions that can be important for the structural identification of each compound. The energetic aspects involved in the protonation and gas-phase fragmentation processes were interpreted on the basis of thermochemical data obtained by computational quantum chemistry. Copyright
- Crotti, Antonio E. M.,Bronze-Uhle, Erika S.,Nascimento, Paulo G. B. D.,Donate, Paulo M.,Galembeck, Sergio E.,Vessecchi, Ricardo,Lopes, Norberto P.
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experimental part
p. 1733 - 1741
(2010/08/04)
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- Total synthesis of discodermolide: Optimization of the effective synthetic route
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An efficient and modulable total synthesis of discodermolide (DDM), a unique marine anticancer polyketide is described including related alternative synthetic approaches. Particularly notable is the repeated application of a crotyltitanation reaction to yield homoallylic (Z)-O-ene-carbamate alcohols with excellent selectivity. Advantage was taken of this reaction not only for the stereocontrolled building of the syn-anti methyl-hydroxy- methyl triads of DDM, but also for the direct construction of the terminal (Z)diene. Of particular interest is also the installation of the C13=C14 (Z)-double bond through a highly selective dyotropic rearrangement. The preparation of the middle C8-C14 fragment in two sequential stages and its coupling to the C1-C7 moiety was a real challenge and required careful optimization. Several synthetic routes were explored to allow high and reliable yields. Due to the flexibility and robust character of this approach, it might enable a systematic structural variation of DDM and, therefore, the elaboration and exploration of novel discodermolide structural analogues.
- De Lemos, Elsa,Poree, Francois-Hugues,Bourin, Arnaud,Barbion, Julien,Agouridas, Evangelos,Lannou, Marie-Isabelle,Commercon, Alain,Betzer, Jean-Francois,Pancrazi, Ange,Ardisson, Janick
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supporting information; experimental part
p. 11092 - 11112
(2009/11/30)
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- Synthesis, in vitro pharmacology, structure - Activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6- dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists
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Novel group II metabotropic glutamate receptor (mGluR) antagonists, 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, were discovered by the incorporation of a hydroxy or alkoxyl group onto the C-3 portion of selective and potent group II mGluR agonist 5, (1R,2S,5R,6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Among these compounds, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6- fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid (-)-11be (MGS0039) was a highly selective and potent group II mGluR antagonist with the best pharmacokinetic profile. Compound (-)-11be exhibited high affinities for mGlu 2 (Ki = 2.38 ± 0.40 nM) and mGlu 3 (4.46 ± 0.31 nM) but low affinity for mGluR 7 (Ki = 664 ± 106 nM), and potent antagonist activities for mGlu 2 (IC50 = 20.0 ± 3.67nM) and mGluR 3 (IC50 = 24.0 ± 3.54 nM) but much less potent antagonist activities for mGlu 4 (IC50 = 1740 ± 1080 nM), mGlu 6 (IC50 = 2060 ± 1270 nM), mGlu 1 (IC50 = 93300 ± 14600 nM), and mGluR 5 (IC50 = 117000 ± 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma Cmax: 214 ± 56.7, 932 ± 235, and 2960 ± 1150 ng/mL for 3 mg/kg, 10 mg/kg, and 30 mg/kg, po, respectively) and acceptable blood-brain barrier penetration (brain C max: 13.2 ng/mL for 10 mg/kg, po 6 h). In this paper, we report the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6- dicarboxylic acid derivatives 11 and 12, and pharmacokinetic profiles of several typical compounds.
- Nakazato, Atsuro,Sakagami, Kazunari,Yasuhara, Akito,Ohta, Hiroshi,Yoshikawa, Ryoko,Itoh, Manabu,Nakamura, Masato,Chaki, Shigeyuki
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p. 4570 - 4587
(2007/10/03)
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- Microbial deracemization of α-substituted carboxylic acids: Substrate specificity and mechanistic investigation
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A new enzymatic method for the preparation of optically active α-substituted carboxylic acids is reported. This technique is called deracemization reaction, which provides us with a route to obtain the enantiomerically pure compounds, theoretically in 100% yield starting from the racemic mixture. This means that the synthesis of a racemate is almost equal to the synthesis of the optically active compound, and this concept is entirely different from the commonly accepted one in the asymmetric synthesis. Using the growing cell system of Nocardia diaphanozonaria JCM3208, racemates of 2-aryl- and 2-aryloxypropanoic acid are deracemized smoothly and (R)-form-enriched products are recovered in high chemical yield (>50%). In addition, using optically active starting compounds and deuterated derivatives as well as inhibitors, we have disclosed the fact that a new type of enzyme takes part in this biotransformation, and that the reaction proceeds probably via the same mechanism as that in rat liver.
- Kato, Dai-Ichiro,Mitsuda, Satoshi,Ohta, Hiromichi
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p. 7234 - 7242
(2007/10/03)
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- Convergent enantioselective synthesis of vinigrol, an architecturally novel diterpenoid with potent platelet aggregation inhibitory and antihypertensive properties. 1. Application of anionic sigmatropy to construction of the octalin substructure
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The coupling of building blocks 15 and 36e in the presence of MgBr2·OEt2 at 0 °C proceeds with an exo stereoselectivity (3.2:1) considerably more advantageous for the acquisition of carbinol 37e than in the absence of the additive (exo/endo = 1:5.7). The pivotal transformation that sets all of the relevant stereocenters of the cis-octalin 55 is the oxyanionic-accelerated [3,3]-sigmatropic rearrangement of 37e. A salient feature is the structurally enforced adoption of a boatlike transition state that serves to properly set four vicinal methine hydrogens in an all-cis arrangement. The ensuing conversion of 55 into iodo sulfone 62 has permitted X-ray crystallographic confirmation of all absolute stereochemical assignments since the isopropyl substituent was initially installed enantioselectively via the Evans oxazolidinone protocol. No intramolecular anionic cyclization of 62 to generate the tricyclic framework was seen. This absence of reactivity is attributed to conformational factors that inhibit attainment of the proper SN2 reaction trajectory.
- Paquette, Leo A.,Guevel, Ronan,Sakamoto, Shuichi,Kim In Ho,Crawford, Jason
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p. 6096 - 6107
(2007/10/03)
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- Biphenylamidine derivatives
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The present invention is a biphenylamidine derivative represented by the formula (1) or a pharmaceutically acceptable derivative thereof: and the biphenylamidine derivative or the pharmaceutically acceptable derivative thereof is a novel compound which can be used as a clinically applicable FXa inhibitor.
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Page column 32-33
(2010/11/29)
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- One-Pot Generation and Conversion of Trichloroacetimidates for the Racemization-Free Allylation and Benzylation of α-Hydroxyesters and the Enantiopure Synthesis of a Chiral Diglycole
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Ο-Allylations and Ο-benzylations of α-hydroxy esters (3a-3c) are performed without racemization. The reagents applied, Ο-allyl- and Ο-benzyltrichloroacetimidate (5a, 5b) are prepared and converted in a one-pot-procedure. After protection by benzylation (S)-(-)-ethyl lactate (3a) is converted by a sequence of carbonyl reduction, alcohol activation, ether formation, and deprotection to the optically active diglycole derivative 1a.
- Christoffers, Jens,R??ler, Ulrich
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p. 654 - 658
(2007/10/03)
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- A simple access to trichloroacetimidates
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O - Trichloroacetimidates can be prepared, under mild conditions in high yield and high purity, by reacting the substrate with trichloroacetonitrile in dichloromethane and 50% aqueous potassium hydroxide mixture containing a catalytic amount of tetra-n-butylammonium hydrogen sulfate.
- Patil, Vijay J.
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p. 1481 - 1484
(2007/10/03)
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- Acid-catalysed Benzylation and Allylation by Alkyl Trichloroacetimidates
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Benzyl and allyl trichloroacetimidate (1) and (2) are convenient reagents for the O-alkylation of hydroxy groups under mildly acidic conditions, wich are compatible with imide, ester, and acetal protecting groups.The base-catalyzed addition of benzyl alcohol or allyl alcohol to trichloroacetonitrile provides a simple synthesis of these imidates, but published methods for the recovery of related molecules by distillation leads to variable amounts of a rearranged product, N-alkyl trichloroacetamide.A modified procedure, suitable for the large scale synthesis of (1) and (2) without the need for a distillation step, is reported.The introduction of benzyl and allyl ethers to a variety of carbohydrate derivatives illustrates the potential of these reagents.
- Wessel, Hans-Peter,Iversen, Tommy,Bundle, David R.
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p. 2247 - 2250
(2007/10/02)
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