- Phosphonate as a Stable Zinc-Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
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Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc-binding group (ZBG) variants of this thiol-derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.
- Voos, Katrin,Sch?nauer, Esther,Alhayek, Alaa,Haupenthal, J?rg,Andreas, Anastasia,Müller, Rolf,Hartmann, Rolf W.,Brandstetter, Hans,Hirsch, Anna K. H.,Ducho, Christian
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p. 1257 - 1267
(2021/03/24)
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- Chlorotropylium Promoted Conversions of Oximes to Amides and Nitriles
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Chlorotropylium chloride as a catalyst for the transformations of oximes, ketones, and aldehydes to their corresponding amides and nitriles in excellent yields (up to 99 %) and in short reaction times (mostly 10–15 min). Oximes were electrophilically attacked on the hydroxyl oxygen by chlorotropylium. The produced tropylium oxime ethers were the key intermediates, of which the ketoxime ether led to amide through Beckmann rearrangement, and the aldoxime ether led to nitrile by nitrogen base DBU assisted formal dehydration. This chlorotropylium activation protocol offered general, mild, and efficient avenues bifurcately from oximes to both amides and nitriles by one organocatalyst.
- Xu, Jiaxi,Gao, Yu,Li, Zhenjiang,Liu, Jingjing,Guo, Tianfo,Zhang, Lei,Wang, Haixin,Zhang, Zhihao,Guo, Kai
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p. 311 - 315
(2020/01/25)
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- Dichloroimidazolidinedione-Activated Beckmann Rearrangement of Ketoximes for Accessing Amides and Lactams
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A novel protocol for the activation of the Beckmann rearrangement utilizing the readily available and economical geminal dichloroimidazolidinediones (DCIDs) on a substoichiometric scale (10 mol %) has been developed. A unique self-propagating mechanism for the substoichiometric dichloroimidazolidinedione-activated transformation was proposed and validated. The substrate scope of the developed protocol has been demonstrated by 23 examples with good to excellent yields (mostly 90-98%) in a short time (mostly 10-30 min), including a substrate for synthesizing the monomer of nylon-12 and a complicated steroidal substrate on a preparative scale. This research not only unveils for the first time the synthetic potential of substoichiometric amounts of dichloroimidazolidinediones in promoting chemical transformation but also offers yet another important illustration of the self-propagating cycle in the context of the Beckmann rearrangement activated by a structurally novel organic promoter.
- Gao, Yu,Liu, Jingjing,Li, Zhenjiang,Guo, Tianfo,Xu, Songquan,Zhu, Hui,Wei, Fulan,Chen, Siming,Gebru, Hailemariam,Guo, Kai
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p. 2040 - 2049
(2018/02/23)
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- Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases
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Secreted virulence factors like bacterial collagenases are conceptually attractive targets for fighting microbial infections. However, previous attempts to develop potent compounds against these metalloproteases failed to achieve selectivity against human
- Sch?nauer, Esther,Kany, Andreas M.,Haupenthal, J?rg,Hüsecken, Kristina,Hoppe, Isabel J.,Voos, Katrin,Yahiaoui, Samir,Els?sser, Brigitta,Ducho, Christian,Brandstetter, Hans,Hartmann, Rolf W.
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supporting information
p. 12696 - 12703
(2017/09/25)
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- Generation of the Methoxycarbonyl Radical by Visible-Light Photoredox Catalysis and Its Conjugate Addition with Electron-Deficient Olefins
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Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl structural motif by a conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl radical species to electron-deficient olefins is heavily influenced by the electronic nature of the acceptor, behavior similar to that exhibited by nucleophilic alkyl radicals.
- Slutskyy, Yuriy,Overman, Larry E.
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supporting information
p. 2564 - 2567
(2016/07/06)
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- An expeditious synthesis of imides from phthalic, maleic and succinic anhydrides and chemoselective C=C reduction of maleic amide esters
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Phthalic, maleic and succinic anhydrides have been reacted with aromatic amines to obtain the corresponding monoacid monoamides. The latter have been each transformed into the corresponding cyclic imide derivatives by treating with SOCl2. Alternatively, anhydrides have been reacted with methanolic KOH to obtain monomethyl ester derivatives which on reaction with aromatic amines in the presence of EDC. HCl and HOBt give cyclic imide derivatives. Reaction of monoacid monoamides independently, with SOCl 2 at 0-5°C give the monoamide monoester derivatives. Treatment of monoamide monoester of malic anhydride with NaBH4 leads to the unusual reduction of C=C grouping as well as the carbonyl group of the ester group to from monoamide monoalcohol of succinic anhydride. Preparation of monoamide monoalcohol of succinic anhydride can also be achieved by chemoselective reduction of monoamide monoester of malic anhydride with Mg turnings yielding monoamide monoester of succinic anhydride followed by reduction of the latter with NaBH4.
- Kumar, Padam Praveen,Reddy, Y. Dathu,Kumari, Y. Bharathi,Devi, B. Rama,Dubey
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p. 392 - 398
(2014/05/06)
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- A facile and green synthesis of N-substituted imides
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Anhydrides 1, 6 and 10 have been reacted, independently, with aromatic primary amines 2 in solid phase by simple physical grinding of reactants with p-toluenesulphonicacid as a catalyst to yield corresponding open chain derivatives, monoacid monoamides3,7 and 11 respectively. The latter have each been transformed into the corresponding cyclic derivatives, i.e. imides 5, 9 and 13 respectively in solid phase by simple physical grinding of each with K 2CO3, alkylating agent and tetrabutylammoniumbromide as a catalyst with short reaction times. These cyclic imides can also be obtained by physical grinding of each of 3, 7 and 11 with dicyclohexylcarbodimide as a dehydrating agent in solid phase.
- Kumar, Padam Praveen,Rama Devi,Dubey
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p. 1166 - 1171
(2013/09/24)
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- Derivatives of aryl amines containing the cytotoxic 1,4-dioxo-2-butenyl pharmacophore
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Several series of compounds containing the 1,4-dioxo-2-butenyl moiety have been prepared as candidate cytotoxins, including the methyl N-arylmaleamates, methyl N-arylfumaramates, and N-arylmaleimides. In addition, the N-arylisomaleimides were synthesized which are the structural isomers of N-arylmaleimides. These compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. Methyl N-arylfumaramates showed the highest cytotoxic potencies and, in particular, methyl N-(3,4-dichlorophenyl)fumaramate is six times more potent than melphalan towards L1210 cells and is equipotent with this drug in the Molt 4/C8 assay. Electrophilicity of compounds under investigation was demonstrated by carrying out thiolation using model benzyl mercaptan on representative compounds. Methyl N-(3,4-dichlorophenyl)fumaramate and methyl N-(4-chlorophenyl)maleamate inhibited human N-myristoyltransferase, a possible molecular target, in high micromolar range. QSAR and molecular modeling revealed some correlations between different structural features of a number of the molecules and cytotoxic potencies. Methyl N-arylfumaramates were well tolerated in mice in comparison to the analogs in other series of compounds tested. The data obtained in this investigation affords guidelines for preparing new series of molecules with greater potencies.
- Jha, Amitabh,Mukherjee, Chandrani,Prasad, Ashok K.,Parmar, Virinder S.,Vadaparti, Manjula,Das, Umashankar,De Clercq, Erik,Balzarini, Jan,Stables, James P.,Shrivastav, Anuraag,Sharma, Rajendra K.,Dimmock, Jonathan R.
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supporting information; experimental part
p. 1510 - 1515
(2010/06/16)
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- Antibacterial activity of a novel series of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione derivatives - An extended structure-activity relationship study
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Compounds containing 3-bromo-2,5-dihydro-1H-2,5-pyrroledione and indole substructures were found to have antibacterial activity against resistant strains of Staphylococcus aureus and some other Gram positive bacteria. The investigated compounds exhibit mi
- Mahboobi, Siavosh,Eichhorn, Emerich,Winkler, Matthias,Sellmer, Andreas,Moellmann, Ute
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p. 633 - 656
(2008/09/19)
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- Novel malonamide derivatives as potent κ opioid receptor agonists
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A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective κ opioid receptor agonists.
- Chu, Guo-Hua,Gu, Minghua,Cassel, Joel A.,Belanger, Serge,Graczyk, Thomas M.,DeHaven, Robert N.,Conway-James, Nathalie,Koblish, Michael,Little, Patrick J.,DeHaven-Hudkins, Diane L.,Dolle, Roland E.
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p. 1951 - 1955
(2008/02/02)
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- Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors
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Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. A mercaptoamide functionality was designed as a bidentate zinc chelator and incorporated into the hydroxamic acid based SAHA (1) scaffold in order to identify non-hydroxamate compounds as potential inhibitors of histone deacetylases. Two sets of mercaptoamides 2 and 3 with varying spacer length were synthesized and their HDAC inhibitory activity was evaluated. Low micromolar inhibition was observed for mercaptoamides 2e, 3b, and 3d.
- Anandan, Sampath-Kumar,Ward, John S.,Brokx, Richard D.,Bray, Mark R.,Patel, Dinesh V.,Xiao, Xiao-Xi
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p. 1969 - 1972
(2007/10/03)
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- Amide derivatives and methods of their use
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Amide derivatives of the general formulae Ia and Ib: are disclosed. Pharmaceutical compositions containing these compounds, and methods for their use, inter alia, for treating and/or preventing gastrointestinal disorders, pain, and pruritus are also disclosed.
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Page/Page column 37
(2008/06/13)
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- Cyanuric chloride as a mild and active Beckmann rearrangement catalyst
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The first general organocatalytic Beckmann rearrangement of ketoximes into amides has been realized by the catalytic use of cyanuric chloride. Furthermore, acids such as HCl and ZnCl2 are effective as cocatalysts with cyanuric chloride. For example, azacyclotridecan-2-one, which is synthetically useful as a starting material for nylon-12, was prepared in quantitative yield by the Beckmann rearrangement of cyclododecanone oxime (100 mmol scale) catalyzed by cyanuric chloride (0.5 mol %) and ZnCl2 (1 mol %). Copyright
- Furuya, Yoshiro,Ishihara, Kazuaki,Yamamoto, Hisashi
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p. 11240 - 11241
(2007/10/03)
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- Anionic hetero[3,3] and [3,5][ rearrangements of hydroxylamine derivatives accompanied with N-O bond cleavage
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Aromatic and aliphatic N,O-divinylhydroxylamine systems generated in situ from hydroxylamine derivatives smoothly undergo [3,3] rearrangement. The base-catalyzed formation and rearrangement of enolates or dienolates of N-aryl-O-acylhydroxylamines, N,O-dia
- Endo,Uchida,Hizatate,Shudo
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p. 1096 - 1105
(2007/10/02)
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- Novel Efficient Synthesis of 1-Ethoxyvinyl Esters Using Ruthenium Catalysts and Their Use in Acylation of Amines and Alcohols: Synthesis of Hydrophilic 3'-N-Acylated Oxaunomycin Derivatives
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A novel and efficient synthesis of 1-ethoxyvinyl esters 3a-i from carboxylic acids 4a-i and ethoxyacetylene 5 by using a catalytic amount of ruthenium complex 2> 6f has been developed.These reagents reacted smoothly with amines and alcohols to give the corresponding N- and O-acylated compounds in excellent yields.This acylation method has been applied to the synthesis of hydrophilic 3'-N-acylated oxaunomycin derivatives 13a,b.
- Kita, Yasuyuki,Maeda, Hiroshi,Omori, Kana,Okuno, Takayuki,Tamura, Yasumitsu
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p. 2999 - 3006
(2007/10/02)
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- Anionic [3,3]-sigmatropic rearrangement of N-phenyl-O-acylhydroxylamines to o-aminophenylcetic acids
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N-Phenyl-O-acylhydroxylamines rearrange under basic conditions to afford o-aminophenylacetic acids. The rearrangement can be rationalized in terms of [3,3]-sigmatropic shifts of an enolized N-phenyl-O-acylhydroxyl-amine.
- Endo, Yasuyuki,Hizatate, Shoji,Shudo, Koichi
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p. 2803 - 2806
(2007/10/02)
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- Nickel(0) induzierte und katalysierte CC-Verknuepfungen von Phenylisocyanat mit funktionalisierten Alkenen
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Monosubstituted alkenes RCH=CH2 (R=OEt (Ia), SPh (Ib), CO2Me (Ic)) react with phenyl isocyanate on (Lig)Ni0 systems to form tricyclohexylphosphane-5-azanickelacyclopentan-4-one-derivatives (V).It is shown that the complexes V are intermediates in the catalytic CC coupling reaction.Further reactions by the system is dependent upon the nature of R.Thus when R=OEt (Ia) a β-elimination is induced, which ultimately leads to 3-ethoxyacrylic acid anilide (XIa), the unsaturated product of a 1/1 CC coupling.On the other hand, when R=CO2Me (Ic) further insertion of isocyanate occurs, to give 1,5-diphenyl-2,6-dioxo-hexahydropyrimidine-4-acidmethylester (XII).Characteristic features are descriebed, and the reaction mechanisms are discussed.
- Hoberg, Heinz,Guhl, Dieter
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p. 245 - 258
(2007/10/02)
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- KINETICS AND MECHANISM OF REVERSIBLE, BASE-CATALYSED RING CLOSURE OF 3-(METHOXYCARBONYL)PROPIONANILIDE AND O-(METHOXYCARBONYLMETHYL)-N-PHENYLCARBAMATE
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The rate constants of reversible, base-catalysed ring closure of 3-(methoxycarbonyl)propionanilide (I) and O-(methoxycarbonylmethyl)-N-phenylcarbamate (II) to 1-phenyl-2,5-pyrrolidinedione (III) and 3-phenyl-2,4-oxazolidinedione (IV), respectively, and the rates of solvolyses of the cyclization products III and IV in water and methanol have been measured.In both cases, an equilibrium is established between the starting ester and the cyclization product in methoxide solutions which is strongly shifted in favour of the starting ester.In the case of ester II in methoxidesolutions, the cyclization is followed by a much slower splitting of the cyclization product to give glycolic acid anilide.The effects of the group X=NH, CH2, O, S in the esters RNHCOXCH2COOCH3 on the rates of the cyclization and solvolysis of the cyclization products is discussed.
- Kavalek, Jaromir,Machacek, Vladimir,Svobodova, Gabriela,Sterba, Vojeslav
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p. 1005 - 1011
(2007/10/02)
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- Borane-Methyl Sulfide Reductive Cyclization of ω-Ester Alkylamides: A Convenient Synthesis of N-Substituted Cyclic Amines
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Borane-methyl sulfide (BMS) reduction of variously N-substituted succinamic and glutaramic esters affords the corresponding N-substituted pyrrolidines and piperidines in high yields.The limitations, mainly caused by steric hinderance around the amine nitrogen, and putative intermediates involved in this conversion, as detected by incomplete reaction and/or synthesis followed by BMS reduction, indicate that cyclization and amide reduction successfully compete with ester reduction to afford the N-substituted cyclized amines.
- Venuti, Michael C.,Ort, Oswald
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p. 985 - 988
(2007/10/02)
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