- Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
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Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
- Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
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p. 4623 - 4661
(2021/05/07)
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- N-(4-acetamidophenyl)-5-acetylfuran-2-carboxamide as a novel orally available diuretic that targets urea transporters with improved PD and PK properties
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Urea transporters (UTs) have been identified as new targets for diuretics. Functional deletion of UTs led to urea-selective urinary concentrating defects with relative salt sparing. In our previous study, a UT inhibitor with a diarylamide scaffold, which is denoted as 11a, was demonstrated as the first orally available UT inhibitor. However, the oral bioavailability of 11a was only 4.38%, which obstructed its clinical application. In this work, by replacing the nitro group of 11a with an acetyl group, 25a was obtained. Compared with 11a, 25a showed a 10 times stronger inhibitory effect on UT-B (0.14 μM vs. 1.41 μM in rats, and 0.48 μM vs. 5.82 μM in mice) and a much higher inhibition rate on UT-A1. Moreover, the metabolic stability both in vitro and in vivo and the drug-like properties (permeability and solubility) of 25a were obviously improved compared with those of 11a. Moreover, the bioavailability of 25a was 15.18%, which was 3 times higher than that of 11a, thereby resulting in significant enhancement of the diuretic activities in rats and mice. 25a showed excellent potential for development as a promising clinical diuretic candidate for targeting UTs to treat diseases that require long-term usage of diuretics, such as hyponatremia.
- Ge, Zemei,He, Jinzhao,Li, Min,Li, Runtao,Li, Xiaowei,Wang, Shuyuan,Xu, Yue,Yang, Baoxue,Zhang, Shun,Zhao, Yan,Zhou, Hong
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- Probing 2H-Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors
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The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so-far underrepresented aza-2H-indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC50 values in the range of 500 nm. In a comparative computational study, these data were analyzed and rationalized in light of docking studies.
- Schoene, Jens,Gazzi, Thais,Lindemann, Peter,Christmann, Mathias,Volkamer, Andrea,Nazaré, Marc
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p. 1514 - 1527
(2019/08/07)
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- Selective cleavage of the N-propargyl group from sulfonamides and amides under ruthenium catalysis
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The selective cleavage of the N-propargyl group from sulfonamides and amides under ruthenium catalysis is described. The reaction tolerates a broad range of functional groups, and the desired products were obtained in 10–95% yield.
- Wang, Jingjing,Li, Feng,Pei, Wenlong,Yang, Mixue,Wu, Yidan,Ma, Danyang,Zhang, Furong,Wang, Jianhui
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supporting information
p. 1902 - 1905
(2018/04/19)
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- METHODS OF INHIBITING BACTERIAL VIRULENCE AND COMPOUNDS RELATING THERETO
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The present invention relates to compounds and methods for the treatment of bacterial infections. Because their mechanism of action does not involve killing of bacteria or inhibiting their growth, the potential for these compounds to induce drug resistance in bacteria is minimized. Through inhibiting bacterial virulence, the present invention provides a novel means of treating bacterial infections.
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Paragraph 0196; 0200
(2017/01/31)
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- Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors
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We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.
- Elgaher, Walid A. M.,Sharma, Kamal K.,Haupenthal, J?rg,Saladini, Francesco,Pires, Manuel,Real, Eleonore,Mély, Yves,Hartmann, Rolf W.
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supporting information
p. 7212 - 7222
(2016/08/24)
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- A convenient and benign synthesis of sulphonamides in PEG-400
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A simple and convenient method is reported for the synthesis of a series of sulphonamides in PEG-400 using potassium carbonate as the base. The reaction is carried out in a heterogeneous medium and consequently product recovery is simple. The desired products with a variety of aromatic amines could be synthesized in a short reaction time in good yield. The PEG could be recovered for reuse.
- Das, Pranab Jyoti,Sarmah, Bhaskar
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p. 189 - 191
(2015/02/19)
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- Ionic liquid-supported synthesis of sulfonamides and carboxamides
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An ionic liquid-supported aldehyde was designed and converted to ionic liquid-supported secondary aryl amines through reductive amination. The reaction of ionic liquid-supported aryl amines with sulfonyl chlorides and acid chlorides, respectively, followed by cleavage using trifluoroacetic acid (TFA) afforded sulfonamides and caboxamides. To introduce additional diversity in the synthesis of sulfonamides and caboxamides, ionic liquid-supported iodosubstituted aryl amine was synthesized using the same strategy, and underwent Suzuki coupling reaction, followed by reaction with a methanesulfonyl chloride to generate the corresponding biaryl sulfonamide. The advantages of the protocol over solid-phase synthesis are homogeneous reaction medium, high loading, easy separation of products, and characterization of intermediates.
- Muthayala, Manoj Kumar,Chhikara, Bhupender S.,Parang, Keykavous,Kumar, Anil
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experimental part
p. 60 - 65
(2012/02/04)
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- ZnO and ZnO-nanoparticles: Efficient and reusable heterogeneous catalysts for one-pot synthesis of N-acylsulfonamides and sulfonate esters
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Commercially available and preparative ZnO nanoparticles are reported as efficient and reusable catalysts for the chemoselective synthesis of N-acylsulfonamides and sulfonate esters. A one-pot sequential sulfonylation and acylation of amines took place to afford the N-acylsulfonamides in excellent yields under solvent-free conditions. The ZnO catalyst can be reused for without significant loss of catalytic activity.
- Tamaddon, Fatemeh,Sabeti, Mohammad Reza,Jafari, Abbas Ali,Tirgir, Farhang,Keshavarz, Elham
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experimental part
p. 41 - 45
(2012/01/12)
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- CsF-Celite as an efficient heterogeneous catalyst for sulfonylation and desulfonylation of heteroatoms
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CsF-Celite is found to be as an efficient reusable catalyst for sulfonylation and desulfonylation of heteroatoms. Sulfonamides and N-acylsulfonamides deprotect efficiently in the presence of CsF-Celite under solvent free conditions to give the free amines or amides in good to excellent yields.
- Tamaddon, Fatemeh,Nasiri, Alireza,Farokhi, Somayeh
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experimental part
p. 1477 - 1482
(2012/06/18)
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- Solvent hydrogen bonding and structural effects on nucleophilic aromatic substitution reactions. Part-2: Reaction of benzenesulphonyl chloride with anilines in propan-2-ol/2-methylpropan-2-ol mixtures
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Substitution reactions of fourteen para- and meta-substituted anilines with benzenesulphonyl chloride in different mole fractions of propan-2-ol in 2-methylpropan-2-ol have been investigated conductometrically. The second order rate constants correlates satisfactorily with pKa values of the anilines and also with the Hammett's substituent constant. The para-substituted anilines shows a satisfactory correlation with Charton's LDR equation. The results of these correlations indicate the formation of an electron deficient transition state. The rate data correlate satisfactorily with macroscopic solvent parameters such as relative permittivity, εr and polarity, ETN. Multiple correlation analysis of the rate data via Kamlet-Taft's solvatochromic parameters reveals that the solvent dipolarityfpolarizability plays a dominant role in governing the reactivity.
- Bhuvaneshwari,Elango
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experimental part
p. 233 - 241
(2010/04/05)
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- Solvent hydrogen bonding and structural effects on nucleophilic substitution reactions: Part 3. Reaction of benzenesulfonyl chloride with anilines in benzene/ propan-2-ol mixtures
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Substitution reactions of 13 para- and meta-substituted anilines with benzene-sulfonyl chloride in varying mole fractions of benzene in propan-2-ol have been investigated conductometrically, The second-order rate constants correlate well with pKa values of anilines and with the Hammett's equation. The negative Hammett reaction constant indicates the formation of an electron-deficient transition state. The rate data correlate satisfactorily with macroscopic solvent parameters such as relative permittivity, εr, and polarity, ETN. Correlation of rate data with Kamlet-Taft solvatochromic parameters (α, β, π*) suggests that both the specific and nonspecific solute-solvent interactions influence the reactivity.
- Bhuvaneshwari,Elango
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p. 657 - 663
(2008/09/17)
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- Solvent hydrogen bonding and structural effects on nucleophilic substitution reactions. Part-1: Reaction of benzenesulphonyl chloride with anilines in benzene/2-methylpropan-2-ol-mixtures
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Substitution reactions of eleven para- and meta-substitutcd anilines with benzencsulphonyl chloride in different mole fractions of benzene in 2-methylpropan-2-ol have been investigated conductometrically. The second order rate constants don't correlate either with pK values of the anilines or with the Hammett's and its modified equations. The para-substituted anilines shows a satisfactory correlation with Charton's LDR equation and the results indicate the formation of an electron deficient transition state. The rate data correlate satisfactorily with macroscopic solvent parameters such as relative permittivity, εr, and polarity, ETN. Multiple correlation analysis of the rate data via Kamlet-Taft's solvatochromic parameters reveals that the solvent hydrogen bond donor property plays a dominant role in governing the reactivity.
- Bhuvaneshwari,Elango
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experimental part
p. 1227 - 1233
(2009/12/31)
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- Sulfur-containing secondary para-phenylenediamines dye compositions comprising such para-phenylenediamines, processes, and uses thereof
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The present disclosure relates to a novel family of sulfur-containing secondary para-phenylenediamines, to processes for preparing them, to compositions for dyeing keratin fibers, for example keratin fibers such as the hair, comprising, in a suitable dyeing medium, at least such one sulfur-containing secondary para-phenylenediamine. The present disclosure also relates to processes for dyeing keratin fibers with the compositions according to the present disclosure and to multi-compartment dyeing kits containing such compositions.
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Page/Page column 25
(2010/02/15)
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- Effect of para substitution on dissociation of N-phenylbenzenesulfonamides
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The reaction of substituted anilines and benzenesulfonyl chlorides has been used to prepare 49 substituted N-phenylbenzenesulfonamides of general formula 4-X-C6H4SO2NHC6H4-Y- 4′. Their purity was checked by elemental analysis. The substituents X and Y include H, CH3, CH3O, Cl, Br, CN, and NO2. The dissociation constants of all compounds were determined by potentiometric titration in methanol, acetonitrile, N,N-dimethylformamide, and pyridine. The obtained dissociation constants, pKHA, were correlated with various sets of substituent constants. It was found that the effects of substituents X and Y on the dissociation are best described by using the Hammett equation with σp constants and the Yukawa-Tsuno equation with σp- and σp constants, respectively. This result confirms the direct conjugation of Y substituent with the reaction centre. The explained variability using the additive model was above 96% in all the solvents used. The data also provided information about the transmission effect of the SO2 group. The average dissociation constants were further processed by the latent variables methods, principal components and conjugated deviations analyses.
- Mansfeld, Martin,Parik, Patrik,Ludwig, Miroslav
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p. 1479 - 1490
(2007/10/03)
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- Antifungal activities of N-arylbenzenesulfonamides against phytopathogens and control efficacy on wheat leaf rust and cabbage club root diseases.
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A set of N-arylbenzenesulfonamides with various substituents at the arylamine and benzenesulfonyl positions were prepared, and their antifungal properties were measured in vitro against such plant pathogenic fungi as Pythium ultimum, Phytophthora capsici, Rhizoctonia solani, and Botrytis cinerea. Compounds 3, 4, 8, 9, 10, 14, 16, 18, 20, 21, 24 and 27 had antifungal activity over a broad spectrum of the phytopathogenic fungi tested, where 50% of inhibition (ED50) was in the range of 3-15 microg/ml. Based on the in vitro activity, six derivatives (3, 4, 10, 18, 21 and 27) were selected and tested further for their fungicidal efficacy in vivo. The fungicidal efficacy of 10, 21 and 27 had a disease control value of over 85% at 50 microg/ml against wheat leaf rust, while that of 4 was selective against cabbage club root disease.
- Kang, Jae Gon,Hur, Jong Hyun,Choi, Sung Jun,Choi, Gyung Ja,Cho, Kwang Yun,Ten, Leonid N,Park, Ki Hun,Kang, Kyu Young
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p. 2677 - 2682
(2007/10/03)
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- Fibrinogen receptor antagonists
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Fibrinogen receptor antagonists of the general formula: and which includes, for example, the compounds of formula STR1 are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, and preventing thrombus or embolus formation.
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- N- and 2-Substituted N-(Phenylsulfonyl)glycines as Inhibitors of Rat Lens Aldose Reductase
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A variety of N-(phenylsulfonyl)-N-phenylglycines 5, N-(phenylsulfonyl)-2-phenylglycines 6, and N-(phenylsulfonyl)anthranilic acids 7 were prepared as analogues of the N-(phenylsulfonyl)glycine 1 aldose reductase inhibitors.In the rat lens assay, several derivatives of 5 display greater inhibitory activity than the corresponding glycines 1, suggesting that N-phenyl substitution enhances affinity for aldose reductase.Enzyme kinetic evaluations of the 4-benzoylamino analogues of 5 and 1 demonstrate that these compounds produce inhibition by the same mechanism.However, the significant differences in relative inhibitory potencies between compounds of series 5 and 1 may indicate that these compounds do not interact with the inhibitor binding site in precisely the same manner.Evaluation of the individual enantiomers of series 6 reveals that the S isomers are substantially more active than the corresponding R isomers.Also, with the exception of the naphthalene analogue 6n, the S stereoisomers of this series display greater inhibitory potencies than the glycines 1.The anthranilates 7 generally are less active than the glycines 1, demonstrating that direct incorporation of an aromatic ring in the glycine side chain may result in a decrease in affinity for aldose reductase.
- DeRuiter, Jack,Borne, Ronald F.,Mayfield, Charles A.
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p. 145 - 151
(2007/10/02)
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- Nitration of the Acetanilide-type Compounds
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Some aromatic compounds containing the imino group (NH) were nitrated in acetic acid or anhydride, and the ortho/para ratios were measured.N-Methyl derivatives of the aforementioned compounds are much less reactive when nitrated under comparable conditions and give significantly lower o/p ratios.These results along with the literature data support the hypothesis that the acetanilide-type compounds are nitrated via N-nitro intermediates.
- Daszkiewicz, Zdzislaw,Kyziol, Janusz B.
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- ANALYSIS OF SUBSTITUENT AND SOLVENT EFFECTS ON DISSOCIATION OF N-PHENYLBENZENESULPHONAMIDES
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The potentiometric titration in water, methanol, dimethyl sulphoxide, dimethylformamide, and acetonitrile has been used for determination of pK values of 13 N-arylbenzenesulphonamides.The validity of the Hammett and Yukawa-Tsuno models using several sets of substituent constants has been evaluated by the test to check adequacy of the regression function and by the factor analysis.It has been found that the substituent effects in solvents must be interpreted with regard to the experimental method used, solvent, set of the substituent constants, as well as the model equation ETR.The dependence of the Hammett reaction constants on the solvent has been analyzed and reveals a preferred stabilization of the conjugated base through hydrogen bonds.Direct conjugation of the reaction centre with the substituent and with different extent of the solvent-dependence with the 4-CN and 4-NO2 derivatives have been observed.
- Ludwig, Miroslav,Pytela, Oldrich,Javurkova, Helena,Vecera, Miroslav
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p. 2900 - 2908
(2007/10/02)
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- Preparation of Nonsymmetrical p-Benzoquinone Diimines for Evaluation as Protein Cleavage Reagents
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In an effort to improve the yield, selectivity, and mildness of reaction conditions employed in protein cleavage with bisalkylating quinone diimines, a series of analogous reagents (1a-h) were prepared.These novel N1,N4 nonsymmetrica
- Holmes, Thomas J.,Lawton, Richard G.
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p. 3146 - 3150
(2007/10/02)
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