- 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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- Robust Photocatalytic Method Using Ethylene-Bridged Flavinium Salts for the Aerobic Oxidation of Unactivated Benzylic Substrates
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7,8-Dimethoxy-3-methyl-1,10-ethylenealloxazinium chloride (1a) was found to be a superior photooxidation catalyst among substituted ethylene-bridged flavinium salts (R=7,8-diMeO, 7,8-OCH2O-, 7,8-diMe, H, 7,8-diCl, 7-CF3 and 8-CF3). Selection was carried out based on structure vs catalytic activity and properties relationship investigations. Flavinium salt 1a proved to be robust enough for practical applications in benzylic oxidations/oxygenations, which was demonstrated using a series of substrates with high oxidation potential, i. e., 1-phenylethanol, ethylbenzene, diphenylmethane and diphenylmethanol derivatives substituted with electron-withdrawing groups (Cl or CF3). The unique capabilities of 1a can be attributed to its high photostability and participation via a relatively long-lived singlet excited state, which was confirmed using spectroscopic studies, electrochemical measurements and TD-DFT calculations. This allows the maximum use of the oxidation power of 1a, which is given by its singlet excited state reduction potential of +2.4 V. 7,8-Dichloro-3-methyl-1,10-ethylenealloxazinium chloride (1 h) can be used as an alternative photocatalyst for even more difficult substrates. (Figure presented.).
- Pokluda, Adam,Anwar, Zubair,Boguschová, Veronika,Anusiewicz, Iwona,Skurski, Piotr,Sikorski, Marek,Cibulka, Radek
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supporting information
p. 4371 - 4379
(2021/04/02)
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- Green synthesis of N-(2-hydroxyethyl)anilines by the selective alkylation reaction in H2O
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Based on our previous work, a safer and more sustainable protocol for the synthesis of N-(2-Hydroxyethyl)anilines has been developed. The synthesis included the selective alkylation reaction of aniline with 2-chloroethanol in H2O, eliminating the need for any catalysts and solvents during synthesis. Comparing with our previous work, the salient features of this methodology are eco-friendliness, economic benefit, and the ease of obtaining target compounds. The selective alkylation reaction in H2O is amenable to scale-up for the synthesis of N-(2-Hydroxyethyl)anilines.
- Guo, Hui,Hao, Jia,Sun, Tingting,Wang, Zuoyao,Cao, Jian,Zhang, Guobao
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- Discovery of dihydropyrazino-benzimidazole derivatives as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs)
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A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure?activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies.
- Szabó, Gy?rgy,Kolok, Sándor,Orgován, Zoltán,Vastag, Mónika,Béni, Zoltán,Kóti, János,Sághy, Katalin,Lévay, Gy?rgy I.,Greiner, István,Keser?, Gy?rgy M.
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- A green and practical reduction of N-(4-chlorophenyl)-2-nitroaniline and its derivatives to corresponding N-substituted-benzene-1,2-diamines using thiourea dioxide
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A new effective approach for synthesizing diverse N-substituted-benzene-1,2-diamines is reported. The treatment of N-substituted-2-nitroanilines with thiourea dioxide in the presence of sodium hydroxide efficiently formed the corresponding N-substituted-benzene-1,2-diamines, including N-(4-chlorophenyl)benzene-1,2-diamine with a good yield of 94%. The by-product is environmentally-friendly urea and is easy to separate from the product by filtration procedure that enhances the convenience of the approach.
- Cui, Jian-Lan,Wang, Ning,Wang, Xiao,Yu, Si-Yuan,Zhong, Cong-Shan
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supporting information
(2020/01/22)
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- Synthesis of o-Nitroarylamines via Ipso Nucleophilic Substitution of Sulfonic Acids
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A mild, efficient, and eco-friendly method for the synthesis of o-nitroarylamine from o-nitroaryl sulfonic acid via ipso nucleophilic aryl substitution by amine is described. The products have been obtained with good yields at room temperature without the assistance of any metal, activating agent, or toxic oxidant. This method is useful for racemization-free synthesis of N-aryl amino acid esters.
- Manne, Srinivasa Rao,Chandra, Jyoti,Mandal, Bhubaneswar
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supporting information
p. 636 - 639
(2019/01/21)
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- Regulating Cofactor Balance In Vivo with a Synthetic Flavin Analogue
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A novel strategy to regulate cofactor balance in vivo for whole-cell biotransformation using a synthetic flavin analogue is reported. High efficiency, easy operation, and good applicability were observed for this system. Confocal laser scanning microscopy was employed to verify that the synthetic flavin analogue can directly permeate into Escherichia coli cells without modifying the cell membrane. This work provides a promising intracellular redox regulatory approach to construct more efficient cell factories.
- Tan, Zhuotao,Zhu, Chenjie,Fu, Jingwen,Zhang, Xiaowang,Li, Ming,Zhuang, Wei,Ying, Hanjie
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supporting information
p. 16464 - 16468
(2018/11/23)
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- CHEMICAL REGENERATION METHOD OF OXIDIZED COENZYME NAD (P)+
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It discloses a chemical regeneration method of oxidized coenzyme NAD(P)+ which is under an oxygen or air atmosphere condition, adding a catalytic amount of bridged flavin, and oxidizing NAD(P)H to obtain NAD(P)+. The catalyst for regeneration of cofactor is cheap and easily available small organic molecule having no noble metal; this regeneration system can regenerate NADH and NADPH; this regeneration system has a wide pH range and temperature range, being applicable to various oxidation reactions catalyzed by nicotinamide-dependent oxidoreductase.
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Paragraph 0053
(2017/07/06)
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- Preparation method of N-(2-nitrophenyl)ethanolamine
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The invention relates to a preparation method of N-(2-nitrophenyl)ethanolamine. The purpose of the invention is to provide the preparation method of N-(2-nitrophenyl)ethanolamine, with the advantages of high yield, high purity, mild production technology and few three wastes. The method comprises the following steps: carrying a heating reaction on o-chloronitrobenzene and ethanolamine in an organic solvent under the action of a catalyst, crystallizing the above prepared product in a solvent, filtering obtained crystals, and drying to obtain the product. The method allows the total yield to reach 95% or above, and has the advantages of few three wastes, simple process, small consumption of raw materials due to recovery of the solvents, and good practicality, and industrial test shows that the method is suitable for industrial production. The N-(2-nitrophenyl)ethanolamine product prepared through the method has the advantages of high purity and good quality, and the preparation method also has the advantages of mild production technology and few three wastes, and fills the technical gap in the domestic synthesis of N-(2-nitrophenyl)ethanolamine.
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Paragraph 0026; 0027; 0028; 0029; 0030; 0031
(2017/02/28)
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- "All-water" one-pot diverse synthesis of 1,2-disubstituted benzimidazoles: Hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' by water
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A new "all-water" tandem arylaminoarylation/arylaminoalkylation- reduction-cyclisation route is reported for one-pot diversity oriented synthesis of regiodefined 1,2-disubstituted benzimidazoles. Water plays a crucial and indispensable role through hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' in the formation of N-mono-aryl/aryl alkyl/alkyl/cycloalkyl o-nitroanilines under metal and base-free conditions to replace the transition metal-based C-N bond formation (aryl amination) chemistry and underlines the origin of regiodefined installation of the diverse selection of aryl, aryl alkyl, and alkyl/cycloalkyl groups as substituents on the benzimidazole scaffold to form the 1,2-disubstituted benzimidazoles. The influence of the hydrogen bond effect of water in promoting the arylaminoarylation reaction under base and metal-free conditions has been realized through observation of inferior yields in D2O compared to that obtained in water during the reaction of o-fluoronitrobenzene with aniline separately performed in water and D2O under similar experimental conditions. Water also provides assistance in promoting the subsequent nitro reduction and in the final cyclocondensation steps. The role of water in promoting the cyclocondensation reaction through hydrogen bonds is realized by the differential product yields during the reaction of mono-N-phenyl-o- phenylenediamine with benzaldehyde performed separately in water and D 2O. The better hydrogen bond donor and hydrogen bond acceptor abilities of water compared to those of the organic solvents are the contributing/deciding factors for making the new water-assisted tandem arylaminoarylation/arylaminoalkylation-reduction-cyclisation strategy for the diversified synthesis of the regiodefined 1,2-disubstituted benzimidazoles effective in an aqueous medium, making it represent a true "all-water chemistry."
- Kommi, Damodara N.,Jadhavar, Pradeep S.,Kumar, Dinesh,Chakraborti, Asit K.
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p. 798 - 810
(2013/04/24)
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- A non-nucleoside triphosphate for powering kinesin-microtubule motility with photo-tunable velocity
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Three non-nucleoside triphosphates, one containing an azobenzene moiety, power a kinesin-microtubule system with high motile activity, with an observed maximum velocity of almost half of that obtained with ATP. The cis-trans photoisomerization of the azobenzene unit allows reversible and repeated control over the motile properties of kinesin.
- Perur, Nishad,Yahara, Masao,Kamei, Takashi,Tamaoki, Nobuyuki
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supporting information
p. 9935 - 9937
(2013/10/22)
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- The mechanism of aromatic nucleophilic substitution reaction between ethanolamine and fluoro-nitrobenzenes: An investigation by kinetic measurements and DFT calculations
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We have studied the kinetics and elucidated the mechanism by DFT calculation of the reaction between ethanolamine (EOA) and 1-fluoro-2,4- dinitrobenzene (DNFB) in acetonitrile and toluene. To determine the contribution of the nitro group, the activation energy of the reaction between ethanolamine and 1-fluoro-2-nitrobenzene (MNFB) vs. DNFB was determined in acetonitrile and calculated by DFT method. Kinetic measurements reveal that the reaction is faster in acetonitrile than in toluene. The reaction follows overall second-order kinetics: first order with respect to both EOA and DNFB which is similar to the results reported for reaction between other primary amines and 1-substituted-2,4-dinitrobenzenes. The calculations by using DFT methods reveal that the mechanism of the reaction involves the formation and decomposition of a Meisenheimer complex (MC). DFT calculations also reveal that the activation energy of the reaction is highest in vacuum and decreases with increasing polarity of the solvent reaching a minimum in acetonitrile. In addition, activation energies obtained by both DFT calculations and experiments show that the reactivity of MNFB is less than that of DNFB showing the effect of the 4-nitro group.
- Jose,Cyriac,Moolayil,Sebastian,George
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supporting information; experimental part
p. 714 - 719
(2012/05/19)
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- Chemoselective sulfide oxidation mediated by bridged flavinium organocatalysts
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The chemoselective oxidation of sulfides to sulfoxides, catalysed by bridged, tetracyclic flavinium catalysts is presented. The flavinium catalysts are easily prepared via a telescoped three-step process. A range of sulfoxides is accessed in excellent yield and chemoselectivity.
- Marsh, Barrie J.,Carbery, David R.
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scheme or table
p. 2362 - 2365
(2010/05/19)
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- Resorcinarene podand with amine-functionalized side arms - Synthesis, structure, and binding properties of a neutral anion receptor
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The synthesis and structure of a neutral resorcinarene host: bearing four amine-functionalized side arms is described. The anion binding properties were investigated in solution by 1H NMR spectroscopic titration and diffusion experiments and in the gas phase by mass spectrometrlc studies. It was observed that in solution 1:2 (host/guest) complexes were formed between the resorcinarene host: and the basic fluoride and acetate anions, whereas in the gas phase 1:1 complexes with other anions (Cl-, HCOO-, NO3-, and BF4-) were detected additionally. Wiley-VCH Verlag GmbH & Co. KGaA.
- Salorinne, Kirsi,Weimann, Dominik P.,Schalley, Christoph A.,Nissinen, Maija
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scheme or table
p. 6151 - 6159
(2010/03/24)
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- Preparation of substituted 1,2,3,4-tetrahydroquinoxalines and 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepines from catalytic Cp*Ir hydrogen transfer N-heterocyclization of anilino alcohols
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The [Cp*IrCl2]2/K2CO3 catalyzed hydrogen transfer N-heterocyclization on a series of anilino alcohols has been investigated. The catalyst (20% loading) converts anilino alcohols to 1,2,3,4-tetrahydroquinoxalines and 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepines in 30-84% isolated yield.
- Todd Eary,Clausen, Dane
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p. 6899 - 6902
(2007/10/03)
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- Synthesis and evaluation of 3-anilino-quinoxalinones as glycogen phosphorylase inhibitors
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A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound.
- Dudash Jr., Joseph,Zhang, Yongzheng,Moore, John B.,Look, Richard,Liang, Yin,Beavers, Mary Pat,Conway, Bruce R.,Rybczynski, Philip J.,Demarest, Keith T.
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p. 4790 - 4793
(2007/10/03)
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- N1,N10-Ethylene-bridged high-potential flavins: Synthesis, characterization, and reactivity
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N1,N10-Ethyleneisoalloxazinium chloride and its 8-Cl-, 7-CF3-, and 3-CH3-7-CF3-substituted analogs were synthesized for the purpose of exhibiting thermal reactivity with organic substrates. The new flavins were characterized spectroscopically and electrochemically, and were found to react with amines, thiols, and phenylhydrazine, the latter case exhibiting catalytic aerobic recycling. Reactions of aliphatic benzylic and cyclopropyl amines with the 7-CF3 analog were also compared to their oxidations by tris(phenanthroline)iron(III). All reactions of the flavinium salts appear to occur through heterolytic rather than homolytic mechanisms.
- Li, Wen-Shan,Zhang, Nanjing,Sayre, Lawrence M.
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p. 4507 - 4522
(2007/10/03)
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- Synthesis and antihistaminic H1 activity of 1,2,5(6)-trisubstituted benzimidazoles
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A number of benzimidazoles, having several substituents on the azole and benzene nuclei and C-2 (methylamino, ethylenediamine, morpholine, piperazine and piperidine) were prepared. Regioselective synthesis was designed for the N1-alkyl substituted benzimidazoles (14-15). X-Ray structure analysis of (14) was also revealed. Compounds were evaluated for their in vitro H1- antihistaminic activity in the isolated guinea-pig ileum method. The compound (11) exhibits best activity.
- Goeker, Hakan,Ayhan-Kilcigil, Guelguen,Tuncbilek, Meral,Kus, Canan,Ertan, Rahmiye,Kendi, Engin,Oezbey, Sueheyla,Fort, Merce,Garcia, Celia,Farre, Antonio J.
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p. 2561 - 2573
(2007/10/03)
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- Unusual reaction of 1,4-diamino-2-nitrobenzene derivatives toward nucleophiles: Catalysis by sodium sulphite
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Unusual substitution of amino group occurs by reactions of some 1,4diamino-2-nitrobenzenes (semipermanent hair dyes) and nucleophiles (NH3, H2O). The reaction is catalyzed by sodium sulfite. The obtained products are suspected of being toxic substances which may be present in cosmetic matrices. Apparently, this reaction is a nucleophilic aromatic substitution but it may be explained by a mechanism involving a tautomeric form of substrate.
- Forlani, Luciano,Boga, Carla,Mazza, Milena,Cavrini, Vanni,Andrisano, Vincenza
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p. 4647 - 4654
(2007/10/03)
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- Process for the preparation of hydroxyalkylaminonitrobenzene derivatives
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The present invention relates to a process for the preparation of compounds of the general formula I STR1 by reaction of compounds of the general formula II STR2 with compounds of the general formula III STR3 in inert aprotic solvents in the presence of a base and subsequent rearrangement of the resulting intermediate compound with an alkali metal hydroxide, characterized in that the intermediate compound is not isolated.
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- Synthesis of 2-imidazolidinylidenepropanedinitrile derivatives as stimulators of gastrointestinal motility. 1
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Ranitidine (1), the histamine H2-receptor antagonist, has been previously reported to increase gastric emptying and gastric motility by inhibition of acetylcholinesterase (AChE) and enhancement of acetylcholine (ACh) release. In order to obtain potent gastroprokinetic agents, a new series of ranitidine derivatives (5-32) possessing a nitrogen atom instead of a sulfur atom (B) was synthesized and their AChE inhibitory activity and potentiating action on electrically evoked contractions of guinea pig ileum were evaluated. Modification of substituents R1 and R2 markedly influenced the activities. In particular, compound 19, {1-[2-[[[5-(piperidinomethyl)-2- furanyl]methyl]amino]-ethyl]-2-imidazolidinylidene}propanedinitrile fumarate, showed 20 and 100 times more potent AChE inhibitory activity and potentiating action on the ileal contraction, respectively, than ranitidine. Furthermore, compound 19 (KW-5092) enhanced gastrointestinal motility in anesthetized rabbits along with a negligible histamine H2-receptor blocking activity.
- Sasho,Obase,Ichikawa,Kitazawa,Nonaka,Yoshizaki,Ishii,Shuto
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p. 572 - 579
(2007/10/02)
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- Substituted arylsulfonamides and benzamides
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This invention relates to substituted arylsulfonamides and benzamides possessing aniarrhythmic activity, to pharmaceutical compositions and to methods for production thereof.
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- Regioselectivity of Photochemical and Thermal Smiles Rearrangements and Related Reactions of β-(Nitrophenoxy)ethylamines
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The ortho, meta, and para isomers of β-(nitrophenoxy)ethylamine (1, 2, and 3, respectively) have been synthesized as hydrochloride salts.The corresponding ortho, meta, and para isomer of β-(nitrophenoxy)ethyl alcohol (4, 5, or 6, respectively), the Smiles rearrangement product, is formed cleanly in alkaline water by a thermal reaction from 1 or 3 and by a photochemical reaction from the triplet state of 2.Photolysis of 1 or 3 does not cause Smiles rearrangement; photoproducts recovered from 1 and 3 show that β-amino group in both cases bonds at the ring carbon atom adjacent to the side chain and meta to the nitro group.The contrast of these results with those reported for photo-Smiles rearrangements of similar systems containing NHPh as the attacking nucleophile and for intermolecular aromatic photosubstitution by alkylamines is discussed.The results support the recently proposed "energy gap" model for predicting regioseelctivity in heterolytic nucleophilic aromatic photosubstitution.
- Wubbels, Gene G.,Halverson, Ann M.,Oxman, Joe D.,Bruyn, Van H. De
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p. 4499 - 4504
(2007/10/02)
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