- 1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-β aggregation crossing the blood-brain barrier
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Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid β fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50 = 90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.
- Prinz, Michaela,Parlar, Sülünay,Bayraktar, Gül?ah,Alptüzün, Vildan,Erciyas, Ercin,Fallarero, Adyary,Karlsson, Daniela,Vuorela, Pia,Burek, Malgorzata,F?rster, Carola,Turunc, Ezgi,Armagan, Guliz,Yalcin, Ayfer,Schiller, Carola,Leuner, Kristina,Krug, Manuel,Sotriffer, Christoph A.,Holzgrabe, Ulrike
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- Synthesis, biological evaluation and molecular docking study of hydrazone-containing pyridinium salts as cholinesterase inhibitors
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A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzy
- Parlar, Sulunay,Bayraktar, Gulsah,Tarikogullari, Ayse Hande,Alptüzün, Vildan,Erciyas, Ercin
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Read Online
- Synthesis of Hydrazinylpyridines via Nucleophilic Aromatic Substitution and Further Transformation to Bicyclo[22.2]octenes Fused with Two N -Aminosuccinimide Moieties
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Efficient and reliable synthesis of substituted hydrazinylpyridines in thick-wall ACE tubes via nucleophilic substitution of a chlorine substituent in different chloropyridines is presented. Hydrazine hydrate and alkylhydrazines were used as nucleophiles and simple alcohols and diethyl ether were the only organic solvents necessary, making the process environmentally and user friendly, potentially reaching 100% atomic efficiency. In the next step, transformations of succinic anhydride moieties fused to the bicyclo[2.2.2]octene framework into succinimide moieties via nucleophilic substitution of oxygens were conducted. As nucleophiles two of the synthesized hydrazinylpyridines (2-hydrazinyl-3-nitropyridine and 2-hydrazinyl-5-nitropyridine) and also hydrazine hydrate, phenylhydrazine, and 4-nitrophenylhydrazine were used. Reactions were again carried out in ACE tubes and only simple alcohols, diethyl ether, and acetone were needed as solvents. One of the prepared bicyclo[2.2.2]octene adducts displayed water solubility thus being a promising candidate for future studies as a novel bidentate ligand for various metal cations in aqueous solutions or acting as an unprecedented halogen bond acceptor.
- Ekar, Jernej,Kranjc, Kri?tof
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p. 1112 - 1120
(2020/10/29)
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- Tetrahydroindazole inhibitors of CDK2/cyclin complexes
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Over 50 tetrahydroindazoles were synthesized after 7-bromo-3,6,6-trimethyl-1-(pyridin-2-yl)-5,6,7,7a-tetrahydro-1H-indazol-4(3aH)-one (3) was identified as a hit compound in a high throughput screen for inhibition of CDK2 in complex with cyclin A. The activity of the most promising analogues was evaluated by inhibition of CDK2 enzyme complexes with various cyclins. Analogues 53 and 59 showed 3-fold better binding affinity for CDK2 and 2- to 10-fold improved inhibitory activity against CDK2/cyclin A1, E, and O compared to screening hit 3. The data from the enzyme and binding assays indicate that the binding of the analogues to a CDK2/cyclin complex is favored over binding to free CDK2. Computational analysis was used to predict a potential binding site at the CDK2/cyclin E1 interface.
- Lee, Jae Chul,Hong, Kwon Ho,Becker, Andreas,Tash, Joseph S.,Sch?nbrunn, Ernst,Georg, Gunda I.
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- Continuous flow synthesis of arylhydrazines: via nickel/photoredox coupling of tert -butyl carbazate with aryl halides
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Nickel/photoredox catalyzed C-N couplings of hydrazine-derived nucleophiles provide a powerful alternative to Pd-catalyzed methods. This continuous-flow photochemical protocol, optimized using design of experiments, achieves these couplings in short residence times, with high selectivity. A range of (hetero)aryl bromides and chlorides are compatible and understanding of process stability/reactor fouling has been discerned. This journal is
- Mata, Alejandro,Tran, Duc N.,Weigl, Ulrich,Williams, Jason D.,Kappe, C. Oliver
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supporting information
p. 14621 - 14624
(2020/12/02)
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- Synthesis and antimicrobial activity of some pyridinium salts
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Some substituted benzylidenehydrazinylpyridinium derivatives bearing benzyl, ethylphenyl and propylphenyl groups on the pyridinium nitrogen were synthesized and screened for possible antibacterial and antifungal activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans using the microdilution method. Antimicrobial test results indicated that compounds containing a 3-phenylpropyl chain displayed the highest antimicrobial activity against Staphylococcus aureus and the compound 3d was the most active in the series against all tested bacteria and fungi strains.
- Alptuezuen, Vildan,Parlar, Sueluenay,Tasli, Hueseyin,Erciyas, Ercin
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experimental part
p. 5203 - 5215
(2010/03/30)
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- THIAZOLIDINE DERIVATIVE AND MEDICINAL USE THEREOF
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A thiazolidine derivative represented by the formula (I) wherein each symbol is as defined in the specification, and a pharmaceutically acceptable salt thereof exhibit a potent DPP-IV inhibitory activity, and can be provided as an agent for the prophylaxis or treatment of diabetes, an agent for the prophylaxis or treatment of obesity and the like.
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- Condensed pyrazole derivatives, process for producing the same and use thereof
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Novel pharmaceutical compositions for inhibiting Th2-selective immune response and pharmaceutical compositions for inhibiting cyclooxygenase comprising condensed pyrazole derivatives represented by the general formula (I): or salts thereof.
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- Pyrazole urea-based inhibitors of p38 MAP kinase: From lead compound to clinical candidate
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We report on a series of N-pyrazole, N′-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5′-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.
- Regan, John,Moss, Neil,Pargellis, Chris,Pav, Sue,Proto, Alfred,Swinamer, Alan,Tong, Liang,Torcellini, Carol,Breitfelder, Steffen,Cirillo, Pier,Gilmore, Thomas,Graham, Anne G.,Hickey, Eugene,Klaus, Bernhard,Madwed, Jeffrey,Moriak, Monica
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p. 2994 - 3008
(2007/10/03)
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- Azaindole derivatives useful as cholesterol biosynthesis inhibitors
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Compounds of the formula I: STR1 wherein X is the residue of an unsubstituted 6-membered aromatic ring having 3 carbon atoms and one nitrogen atom; R1 is C1-6 primary alkyl (free of asymmetric carbon atoms), or isopropyl; R2 is substituted or unsubstituted phenyl, primary or secondary C1-6 alkyl (free of asymmetric carbons), C3-6 cycloalkyl or phenalkyl as defined in the Specification STR2 in which R8 is hydrogen, R9 or M, wherein R9 is a physiologically acceptable and hydrolyzable ester group, and M is a pharmaceutically acceptable cation; are obtained by multi-step processes and are useful as cholesterol biosynthesis inhibitors. 3
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