- Unlocking Amides through Selective C–N Bond Cleavage: Allyl Bromide-Mediated Divergent Synthesis of Nitrogen-Containing Functional Groups
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We report a new set of reactions based on the unlocking of amides through simple treatment with allyl bromide, creating a common platform for accessing a diverse range of nitrogen-containing functional groups such as primary amides, sulfonamides, primary amines, N-acyl compounds (esters, thioesters, amides), and N-sulfonyl esters. The method has potential industrial applicability, as demonstrated through gram-scale syntheses in batch and in a continuous flow system.
- Govindan, Karthick,Chen, Nian-Qi,Chuang, Yu-Wei,Lin, Wei-Yu
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supporting information
p. 9419 - 9424
(2021/11/30)
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- 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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supporting information
p. 4623 - 4661
(2021/05/07)
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- Sulfonamide compound and synthesis method and application thereof
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The invention discloses a synthesis method of a sulfonamide compound represented in a formula (2). According to the method, diazonium salt is used as a reaction raw material, and under the action of an inorganic nitrogen reagent, an inorganic sulfur dioxide reagent, an additive and a phosphine reagent, the diazonium salt is reacted in a solvent at 60-100 DEG C to obtain various sulfonamide compounds. According to the method inorganic salt is used as a nitrogen atom source and a sulfur dioxide source under a metal-free catalytic condition to construct the sulfonamide compound through one step,thereby avoiding the conventional multi-step synthesis of sulfonamide by condensing unstable acid chloride and amine; and the developed sulfonamide synthesis method can be further applied to the synthesis of the arthritis drug celecoxib and the psychotropic drug sulpiride.
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Paragraph 0054-0057
(2019/04/02)
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- Nickel complexes with phosphines and N-R-sulfonyldithiocarbimates ligands: New antifungals for the control of Hemileia vastatrix and Phakopsora pachyrhizi
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Nickel(II) complexes of general formula [Ni(RSO2N = CS2)(PPh3)2] (2a–h) or [Ni(RSO2N = CS2)dppe] (3a–h), where R = methyl (a), ethyl (b), butyl (c), octyl (d), phenyl (e), 4-isopropylphenyl (f), 4-tert-butylphenyl (g), 2-naphthyl (h), PPh3 = triphenylphosphine and dppe = 1,2-bis(diphenylphosphine)ethane were prepared, from which six are new substances (2f–h and 3f–h). The new compounds were characterized by elemental analysis of C, H, N and Ni, and by IR, UV–Vis and 1H, 13C and 31P NMR spectroscopies. The data were consistent with the formation of square planar nickel(II) complexes with mixed ligands, what was confirmed by single crystal X-ray diffraction studies on compounds 2f and 2h. These complexes present intramolecular Ni–H–C anagostic interactions. All complexes inhibited the germination of Hemileia vastatrix and Phakopsora pachyrhizi, the causal agents of devastating diseases on soybean and coffee cultures. The most active compounds presented IC90 values as low as 405 μM against H. vastatrix, and 280 μM against P. pachyrhizi. Thus, the title compounds are target molecules for the development of new agrochemicals against the Asian soybean rust and Coffee leaf-rust diseases.
- Vidigal, Antonio E.C.,Rubinger, Mayura M.M.,de Queiroz, Luan F.,da Silva, Lucas F.,Zambolim, Laércio,Guilardi, Silvana,Souza, Rafael A.C.,Ellena, Javier,Wetler, Emiliana B.,Oliveira, Marcelo R.L.
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p. 724 - 732
(2018/12/11)
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- Metal-free construction of primary sulfonamides through three diverse salts
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In this report, the first metal-free construction of primary sulfonamides through a direct three-component reaction of sodium metabisulfite, sodium azide and aryldiazonium has been established. Readily available inorganic Na2S2O5 and NaN3 were applied as the sulfur dioxide surrogate and nitrogen source respectively. The widely used sulfonamide drugs Celecoxib and Sulpiride, which possess multiple heteroatoms and active hydrogen containing functional groups, are efficiently installed with -SO2NH2 groups at a late stage. Control experiments and kinetic studies demonstrated that aryl radicals, sulfonyl radicals and conjugated phosphine imine radicals are involved in this transformation.
- Wang, Ming,Fan, Qiaoling,Jiang, Xuefeng
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supporting information
p. 5469 - 5473
(2019/01/03)
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- Design, synthesis and biological evaluation of novel phenylsulfonylurea derivatives as PI3K/mTOR dual inhibitors
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Five series of novel phenylsulfonylurea derivatives, 19a–d, 20a–d, 21a–d, 22a–d and 23a–d, bearing 4-phenylaminoquinoline scaffold were designed, synthesized and their IC50 values against four cancer cell lines (HepG-2, A549, PC-3 and MCF-7) were evaluated. Most compounds showed moderate cytotoxicity activity against the cancer cell lines. Structure–activity relationships (SARs) and pharmacological results indicated that introduction of 4-aminoquinoline scaffold and phenylsulfonylurea scaffold were beneficial for anti-tumor activity. Moreover, para-methoxyl substitution of 4-anilino moiety and para-halogen substitution of phenylsulfonylurea have different impacts on different series of compounds. Furthermore, the micromolecule group substitution in the 6-position of the quinoline ring have a slight impact on the cellular activity of the target compounds.
- Zhao, Bingbing,Lei, Fei,Wang, Caolin,Zhang, Binliang,Yang, Zunhua,Li, Wei,Zhu, Wufu,Xu, Shan
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- Highly Chemoselective NH- and O-Transfer to Thiols Using Hypervalent Iodine Reagents: Synthesis of Sulfonimidates and Sulfonamides
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Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.
- Tota, Arianna,St John-Campbell, Sahra,Briggs, Edward L.,Estévez, Gala Ogalla,Afonso, Michelle,Degennaro, Leonardo,Luisi, Renzo,Bull, James A.
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supporting information
p. 2599 - 2602
(2018/05/22)
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- Enabling the Cross-Coupling of Tertiary Organoboron Nucleophiles through Radical-Mediated Alkyl Transfer
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The construction of quaternary centers is a common challenge in the synthesis of complex materials and natural products. Current cross-coupling strategies that can be generalized for setting these centers are sparse and, when known, are typically predicated on the use of reactive organometallic reagents. To address this shortcoming a new, photoredox-Ni dual catalytic strategy for the cross-coupling of tertiary organoboron reagents with aryl halides is reported. In addition to details on the cross-coupling scope and limitations, full screening efforts and mechanistic experiments are communicated.
- Primer, David N.,Molander, Gary A.
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supporting information
p. 9847 - 9850
(2017/08/02)
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- Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays
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Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48?μM and 1.61?μM, respectively. They were much potent than the reference drug ddI (EC50?=?76.0?μM) and comparable to 3TC (EC50?=?2.54?μM). Compound 7a also exhibited the favorable selectivity index (SI?=?80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
- Huang, Boshi,Wang, Xueshun,Liu, Xinhao,Chen, Zihui,Li, Wanzhuo,Sun, Songkai,Liu, Huiqing,Daelemans, Dirk,De Clercq, Erik,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
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p. 4397 - 4406
(2017/07/22)
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- Ruthenium trichloride catalyzed synthesis of 2,3-unsaturated-N-glycosides via Ferrier azaglycosylation
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An efficient, economical and mild protocol for the synthesis of 2,3-unsaturated-N-glycosides has been developed using ruthenium(III) chloride. The Ferrier azaglycosylation of glycals with various N-nucleophiles such as sulfonamides, benzamides, carbamates and N-substituted sulfonamides proceeded smoothly to afford the corresponding 2,3-unsaturated-N-glycosides or ‘N-pseudoglycals’ in good yields (64–98%). High α-anomeric selectivity was observed with N-substituted sulfonamides such as N-benzyl or N-phenyl sulfonamides under similar conditions.
- Reddy, Thurpu Raghavender,Chittela, Sravanthi,Kashyap, Sudhir
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supporting information
p. 9224 - 9229
(2017/09/08)
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- Scandium triflate as an efficient and recyclable catalyst for the deprotection of tert-butyl aryl sulfonamides
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A mild and efficient method for deprotection of tert-butyl sulfonamide groups utilizing Sc(OTf)3 as deprotecting reagent has been developed. A variety of tert-butyl aryl sulfonamides used under these conditions gave the corresponding primary sulfonamides in high yields. The Lewis acid catalyst could be fully recovered and reused with maintained activity after the reactions. Copyright Taylor & Francis, Inc.
- Mahalingam,Wu, Xiongyu,Wan, Yiqian,Alterman, Mathias
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p. 417 - 425
(2007/10/03)
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- Novel N-dealkylation of N-alkyl sulfonamides and N,N-dialkyl sulfonamides with periodic acid catalyzed by chromium(III) acetate hydroxide
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Chromium(III) acetate hydroxide has been found to be an efficient catalyst for N-dealkylation of N-alkyl sulfonamides and N,N-dialkyl sulfonamides to furnish sulfonamides in good to excellent yields with periodic acid in acetonitrile at room temperature.
- Xu, Liang,Zhang, Suhong,Trudell, Mark L.
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p. 1901 - 1904
(2007/10/03)
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- (1-phenyl-2-heteroaryl)ethyl-guanidine compounds as inhibitors of mitochondrial F1F0 ATP hydrolase
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Compounds having the formula (I), and pharmaceutically acceptable salts thereof, are useful for modulating mitochondrial F1F0 ATPase activity and treating ischemic conditions including myocardial infarction, congestive heart failure, and cardiac arrhythmias.
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Page/Page column 16; 64
(2010/11/30)
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- Investigation of structure-activity relationships in a series of glibenclamide analogues
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In this study, the synthesis of 15 new glibenclamide analogues is described. The conformational trends of these analogues were investigated using Monte Carlo conformational analysis. The conformational analysis results resolved the discrepancy between previous molecular modelling simulations of glibenclamide and allowed rationalizing the effect of aqueous environment on the overall conformation. The 3D-QSAR study was carried out with respect to the compounds' ability to antagonize the [3H]-glibenclamide binging in rat cerebral cortex. Superimposition of the antagonists was performed using the conformations derived from atom-by-atom fit to the glibenclamide crystal structure and this alignment was used to develop CoMFA models. CoMFA provided a good predictability: number of PLS components = 2, q2 = 0.876, R 2 = 0.921, SEE = 0.455 and F = 70. Best CoMFA models showed the steric and lipophilic properties as the major interacting forces whilst the electrostatic property contribution was a minor factor.
- Yuriev, Elizabeth,Kong, David C.M.,Iskander, Magdy N.
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p. 835 - 847
(2007/10/03)
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- Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives
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Modifications to the ETA/B mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ETA receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)- 4pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ETA receptor (Ki=0.0042±0.0038 nM) and an ETA/B receptor selectivity up to 29 000 (Ki=130±50 nM for the human cloned ETB receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ETA receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ETA receptor.
- Morimoto,Shimadzu,Kushiyama,Kawanishi,Hosaka,Kawase,Yasuda,Kikkawa,Yamauchi-Kohno,Yamada
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p. 3355 - 3368
(2007/10/03)
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- Concave Macroheterocycles
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Macrocyclic compounds of the general type 2 having a spherical shape and a molecular cavity have been synthesized.A "fold and paste"-type cyclization step generates the macroheterocycles 4,10,11,14, and 21.Since this approach is difficult to apply for O-substituted derivatives, the "spheriphane" 24 was synthesized by intermolecular cyclization.The X-ray structure analysis of 11 shows intermolecular interactions ("dimer formation") in the crystal. Key Words: Concave molecules/ Cyclophanes/ High-dilution principle/ Macrocycles/ Spheriphanes
- Mekelburger, Hans-Bernhard,Gross, Jens,Schmitz, Juergen,Nieger, Martin,Voegtle, Fritz
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p. 1713 - 1722
(2007/10/02)
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