- Discovery and development of 2-aminobenzimidazoles as potent antimalarials
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The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC50 values against P. falciparum 3D7 strain of 42 ± 4 (3c) and 43 ± 2 nM (3g), and high potency against strains resistant to chloroquine (Dd2), artemisinin (Cam3.IIC580Y) and PfATP4 inhibitors (SJ557733), while demonstrating no cytotoxicity against human cells (HEK293, IC50 > 50 μM). The most potent molecule, possessing a 4,5-dimethyl substituted phenol (3r) displayed an IC50 value of 6.4 ± 0.5 nM against P. falciparum 3D7, representing a 12-fold increase in activity from the parent molecule. The 2-aminobenzimidazoles containing a N1-substituted phenol represent a new class of molecules that have high potency in vitro against P. falciparum malaria and low cytotoxicity. They possessed attractive pharmaceutical properties, including low molecular weight, high ligand efficiency, high solubility, synthetic tractability and low in vitro clearance in human liver microsomes.
- Avery, Vicky M.,Challis, Matthew P.,Creek, Darren J.,De Paoli, Amanda,Devine, Shane M.,Kigotho, Jomo K.,MacRaild, Christopher A.,Norton, Raymond S.,Scammells, Peter J.,Siddiqui, Ghizal
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- A Common, Facile and Eco-Friendly Method for the Reduction of Nitroarenes, Selective Reduction of Poly-Nitroarenes and Deoxygenation of N-Oxide Containing Heteroarenes Using Elemental Sulfur
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A transition metal-free, environment-friendly and practical protocol was developed either for the reduction of nitroarenes or for the deoxygenation of N-oxide containing heteroarenes. The reaction proceeded with the use of a non-toxic and cheap feedstock as elemental sulfur in aqueous methanol under relatively mild conditions. Green chemistry credentials were widely favorable compared to traditional and industrial protocols with good E-factors and a low production of waste. The strategy allowed the efficient reduction of a large variety of substituted-nitroarenes including various o-nitroanilines as well as selective reduction of various poly-nitroarenes in excellent yields with a broad substrate scope. The protocol was successfully extended to the deoxygenation of some N-oxide containing heteroarenes, like benzofuroxans, phenazine N,N'-dioxides, pyridine N-oxides, 2H-indazole N1-oxides, quinoxaline N1,N4-dioxides and benzo[d]imidazole N1,N3-dioxides. A gram-scale example for the synthesis of luminol, in green conditions, was reported. A solid mechanism of reaction was proposed from experimental evidences.
- Cerecetto, Hugo,Romero, Angel H.
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supporting information
(2020/03/23)
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- Synthesis method of aminopyridine compounds
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The invention provides a synthesis method of aminopyridine compounds. The synthesis method of the aminopyridine compounds comprises the following steps: under a heating condition, halogenated pyridineorganic matters and an ammoniation reagent are subjected to an ammoniation reaction to obtain an ammoniated product system, wherein in the ammoniation reaction, the temperature of the ammoniation reaction is 200-240 DEG C, and the ammoniation reagent is in a solid state and can be decomposed to generate ammonia gas; and the ammoniated product system is sequentially purified and salified to obtainthe aminopyridine compounds. The synthesis method does not need to add a solvent, so that the yield of three wastes can be greatly reduced; the type of the ammonification reagent and the ammonification reaction temperature are limited during the reaction process, such that the high reaction rate and the high conversion rate can be obtained without the addition of the catalyst, and the purification and salification process after the ammonification reaction is simple and has the good separation effect so as to substantially reduce the production cost and improve the product yield and the product purity. In addition, the synthesis method also has the advantages of good repeatability and the like.
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Paragraph 0053-0054
(2020/10/14)
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- Benzimidazole derivatives, their preparation and their application in medicine and pharmacology (by machine translation)
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The invention relates to a new control or inhibit indocyanine 2, 3 - dioxygenase (IDO) activity of the benzimidazole derivatives, their preparation and their application in medicine and pharmacology. Specifically, the invention relates to a compound of general formula (I) compound of formula and its pharmaceutically acceptable salt, containing the compound or its pharmaceutically acceptable salt of the pharmaceutical composition, the use of the compound or its pharmaceutically acceptable salts for treating and/or preventing the relevance of the IDO-mediated disease, especially a tumor of the method and the compound or its pharmaceutically acceptable salts thereof. The invention also relates to the compound or its pharmaceutically acceptable salt or containing the compound or its pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for treating and/or preventing the relevance of the IDO-mediated disease, in particular of the use of the drug in the tumor. Wherein the general formula (I) of each substituent is as defined in the specification. (by machine translation)
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Paragraph 0136-0137
(2019/07/16)
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- Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis
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GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.
- Miltz, Wolfgang,Velcicky, Juraj,Dawson, Janet,Littlewood-Evans, Amanda,Ludwig, Marie-Gabrielle,Seuwen, Klaus,Feifel, Roland,Oberhauser, Berndt,Meyer, Arndt,Gabriel, Daniela,Nash, Mark,Loetscher, Pius
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p. 4512 - 4525
(2017/07/22)
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- 2, 3-dichloropyridine preparation method
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The present invention discloses a 2, 3-dichloropyridine preparation method comprising the following steps: (1) 2,3-dimethylamide pyridine is dissolved in water, then a caustic soda aqueous solution and a sodium hypochlorite aqueous solution are successively added, after the addition is completed, the mixture is heated for full reaction, after the reaction is completed, the system is adjusted to be neutral or acidic by use of hydrochloric acid, and water is removed by distillation to obtain a 2,3-diaminopyridine crude product; (2) the 2,3-diaminopyridine crude product is dissolved in hydrochloric acid, a catalyst is added, then a sodium nitrite aqueous solution is added dropwise, after the addition is complete, the2,3-diaminopyridine crude product is completely reacted, and after the reaction is completed, a 2, 3-dichloropyridine crude product is obtained by distillation; and (3) the 2, 3-dichloropyridine crude product is added into an organic solvent for complete dissolving, then cooled for recrystallization, crystals are filtered off and dried to obtain a 2, 3-dichloropyridine finished product. The method avoids the problem of very low tendency for side effects of 2-site chlorination, the production process is simple, the reaction is smooth and steady, production cost is low, product yield is high, and product purity is high.
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Paragraph 0024-0026
(2017/02/09)
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- Exploration of relative chemoselectivity in the hydrodechlorination of 2-chloropyridines
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The chemoselectivity of hydrodechlorination in 2-chloropyridine derivatives possessing reduction-sensitive functionalities is examined. The reaction conditions employed tolerate a variety of functionalities illustrating highly chemoselective hydrodechlorination in the presence of nitrile, allyl, terminal olefin, and nitroamine functionalities in excellent yield. Chemoselective deprotection of carboxybenzyl ethers is illustrated in moderate yield.
- Kinarivala, Nihar,Trippier, Paul C.
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supporting information
p. 5386 - 5389
(2015/01/16)
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- Controlling molecular tautomerism through supramolecular selectivity
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We have isolated the stable as well as the metastable tautomers of 1-deazapurine in the solid state by exploiting principles of supramolecular selectivity in the context of cocrystal design.
- Epa, Kanishka,Aakeroey, Christer B.,Desper, John,Rayat, Sundeep,Chandra, Kusum Lata,Cruz-Cabeza, Aurora J.
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p. 7929 - 7931
(2013/09/02)
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- Imidazopyridines: A novel class of hNav1.7 channel blockers
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A series of imidazopyridines were evaluated as potential sodium channel blockers for the treatment of neuropathic pain. Several members were identified with good hNav1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good efficacy (52% and 41% reversal of allodynia at 2 and 4 h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain when dosed orally at 10 mg/kg.
- London, Clare,Hoyt, Scott B.,Parsons, William H.,Williams, Brande S.,Warren, Vivien A.,Tschirret-Guth, Richard,Smith, McHardy M.,Priest, Birgit T.,McGowan, Erin,Martin, William J.,Lyons, Kathryn A.,Li, Xiaohua,Karanam, Bindhu V.,Jochnowitz, Nina,Garcia, Maria L.,Felix, John P.,Dean, Brian,Abbadie, Catherine,Kaczorowski, Gregory J.,Duffy, Joseph L.
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p. 1696 - 1701
(2008/12/23)
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- Synthesis of 2-alkyl-substituted benzimidazoles by thermal decomposition of 2-azidobenzenamines in the presence of an aldehyde
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2-Substituted benzimidazoles were prepared by reaction of 2-azidoaminobenzenes with aldehydes under thermal conditions. The reaction probably proceeds via a sequential imine formation, azide decomposition forming a nitrene, and electrocyclization. Copyright Taylor & Francis Group, LLC.
- Wallace, Jeffery M.,Soederberg, Bjoern C. G.,Hubbard, Jeremiah W.
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p. 3425 - 3439
(2007/10/03)
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- Hair dye compositions and process comprising and utilizing a combination of isatin and aminopyridine derivatives
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The invention relates to a process for dyeing keratinous fibers, comprising the simultaneous or sequential application of a component (A) containing at least one compound of formula (I): STR1 in which: R1 denotes hydrogen, alkyl, acetyl, benzoyl, phenyl or carboxyalyl; R2 and R3 denote a hydrogen, alkyl, hydroxyl, halogen, nitro, alkylphenyl, phenyl or alkoxy; and a component (B) containing at least one compound of formula (II): STR2 in which: R4 denotes a hydrogen atom or a β-hydroxyethyl group; n=0, 1 or 2, and m=0 or 1; as well as its cosmetically acceptable salts; or one compound of formula (III): STR3 in which: R5 denotes a hydrogen atom, a hydroxyl group or a group STR4 R6 denotes a hydroxyl group or a group N STR5 R7 denotes H or NH2, R8 denotes a group STR6 R9 and R10, independently of one another, representing a hydrogen atom, a C1 -C4 alkyl, a group (CH2)p --Z, where p=1 to 4 and Z represents OH, halogen, NH2, NHR' or NHR'R", where R' and R" denote a C1 -C4 alkyl or form a heterocycle with the nitrogen atom to which they are attached; with the proviso that one of R5 to R8 denotes NH2 ; and its cosmetically acceptable salts, as well as to the dyeing agents employed.
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- Diaminopyridine compounds and methods of use
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The present invention relates to compositions and method for inhibiting nonenzymatic cross-linking (protein aging) which contain diaminopyridines and derivates thereof. Accordingly, a composition is disclosed which comprises an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins by reacting with the carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.
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- Pyrido[2,3-c]furoxan as a probable intermediate in the reaction of 2-nitro-3-azidopyridine with amines
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Two parallel reactions, viz., cyclization of 2-nitro-3-azidopyridine to pyrido-[2,3-c]furoxan, which is aminated in the 6 position of the pyridine ring with opening of the furoxan ring, and reduction of the azido group to form 2-nitro-3-aminopyridine, occur in the reaction of 2-nitro-3-azidopyridine with amines. It was established that pyrido[2,3-c]furoxan reacts with amines in aqueous media in the 1-oxide form.
- Kotovskaya,Mokrushina,Postovskii,Polyakova
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p. 480 - 483
(2007/10/02)
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