- Structure-activity relationship study of thiazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors
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Several human diseases are associated with aberrant epigenetic pathways mediated by histone deacetylases (HDACs), especially HDAC6, a class IIb HDACs, which has emerged as an attractive target for neurodegenerative and autoimmune disease therapeutics. In a previous study, we developed the novel HDAC6-selective inhibitor 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) and showed that it has anti-sepsis activity in vivo. In this study, we conducted structure-activity relationship (SAR) studies to optimize the activity and selectivity of HDAC6, synthesizing its derivatives with various aliphatic linker sizes and cap structures. We identified 6u ((E)-N-hydroxy-3-(2-(4-fluorostyryl)thiazol-4-yl)propanamide), which has nanomolar inhibition activity and a 126-fold selectivity for HDAC6 over HDAC1. Through the docking analyses of 6u against HDAC subtypes, we revealed the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Thus, we suggest a new rationale for the design of HDAC6-selective inhibitors.
- Nam, Gibeom,Jung, Jun Min,Park, Hyun-Ju,Baek, Seung Yeop,Baek, Ki Seon,Mok, Hui yeon,Kim, Da Eun,Jung, Young Hoon
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p. 3408 - 3420
(2019/06/25)
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- Domino aryne precursor: Efficient construction of 2,4-disubstituted benzothiazoles
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An aryne precursor with a potential to perform domino aryne chemistry was proposed and synthesized. The reaction of this reagent with benzothioamide derivatives could afford 2,4-disubstituted benzothiazole with sequential incorporation of C-S, C-N, and C-C bonds on the consecutive three positions of the aryne precursor.
- Shi, Jiarong,Qiu, Dachuan,Wang, Juan,Xu, Hai,Li, Yang
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supporting information
p. 5670 - 5673
(2015/05/20)
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- Metal-free, one-pot oxidative conversion of aldehydes to primary thioamides in aqueous media
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One-pot tandem reactions of a variety of aldehydes with aqueous ammonia, molecular iodine, and O,O-diethyl dithiophosphoric acid readily afford the corresponding primary thioamides. This is an inexpensive, practical, and metal-free way of accessing various thioamides from aldehydes in aqueous media. The pure products are obtained simply by filtration followed by successive washing with aqueous sodium thiosulfate and water. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]
- Yadav, Arvind K.,Srivastava, Vishnu P.,Yadav, Lal Dhar S.
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p. 408 - 416
(2014/01/06)
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- Microwave-assisted synthesis of potent PDE7 inhibitors containing a thienopyrimidin-4-amine scaffold
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A series of novel thienopyrimidin-4-amines have been synthesized and evaluated as phosphodiesterase (PDE) inhibitors. A rationale for the observed selectivity against PDE7 has been obtained from molecular modelling studies on the most active compounds. This journal is the Partner Organisations 2014.
- Sanchez, Ana I.,Meneses, Ricardo,Minguez, Jose M.,Nunez, Araceli,Castillo, Rafael R.,Filace, Fabiana,Burgos, Carolina,Vaquero, Juan J.,Alvarez-Builla, Julio,Cortes-Cabrera, Alvaro,Gago, Federico,Terricabras, Emma,Segarra, Victor
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p. 4233 - 4242
(2014/06/10)
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- CuCl-catalyzed radical cyclisation of N-α-perchloroacyl-ketene-N,S- acetals: A new way to prepare disubstituted maleic anhydrides
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The copper-catalyzed radical cyclization (RC) of N-α-perchloroacyl cyclic ketene-N,X(X=O, NR, S)-acetals was studied. While the RC of N-acyl ketene-N,O-acetals was unsuccessful, the 5-endo cyclization of the other ketene acetals provided much better results, with the following order of cyclization efficiency: hexa-atomic cyclic ketene-N,NR-acetalspenta-atomic cyclic ketene-N,S-acetalshexa-atomic cyclic ketene-N,S-acetals. Invariably the catalytic cycle begins with the formation of a carbamoyl methyl radical. This leads to a cascade of reactions, including a radical polar crossover step, which ends with the formation of the maleimide nucleus, or precursors of this. Products from the RC of the hexa-atomic cyclic ketene-N,S-acetals, were efficiently transformed into disubstituted maleic anhydrides.
- Cornia, Andrea,Felluga, Fulvia,Frenna, Vincenzo,Ghelfi, Franco,Parsons, Andrew F.,Pattarozzi, Mariella,Roncaglia, Fabrizio,Spinelli, Domenico
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experimental part
p. 5863 - 5881
(2012/09/22)
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- Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1
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Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7 nM and functional antagonistic effect of 66 nM in a BRET and 12 nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27 μM in cAMP).
- Rist, ystein,Grimstrup, Marie,Receveur, Jean-Marie,Frimurer, Thomas M.,Ulven, Trond,Kostenis, Evi,Hoegberg, Thomas
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scheme or table
p. 1177 - 1180
(2010/06/15)
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- The BF3·OEt2-assisted conversion of nitriles into thioamides with Lawesson's reagent
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A method for the thiolysis of nitriles by applying Lawesson's reagent and facilitated by the addition of boron trifluoride-diethyl ether complex is reported. The method opens an easy access to primary thioamides. Aromatic, benzylic, and aliphatic nitriles were converted into the corresponding thioamides in high to quantitative yields (even in unfavorable cases, e.g., ortho-substitut-ed benzonitriles). The reaction was performed in 1,2-dimethoxyethane-tetrahydrofuran or toluene-diethyl ether solvent mixtures at 20-50°C, and exhibited considerable selectivity in the case of multifunctional nitrile substrates, such as cyanomethyl N-acetylphenylalaninate, benzoylacetonitrile, 4-cyanobenzamide, 4-acetylbenzonitrile, or pent-3-enenitrile. Georg Thieme Verlag Stuttgart.
- Nagl, Michael,Panuschka, Claudia,Barta, Andrea,Schmid, Walther
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experimental part
p. 4012 - 4018
(2009/05/27)
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- Synthesis of (4R,5S)-melithiazols F and I
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Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (8) derived from the (2R,3S)-epoxybutanoate 7 followed by methylation gave the tetrahydro-2-furylidene acetate (-)-9, which was converted into the left-half aldehyde (+)-4. A Wittig reaction between (+)-4 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 5 using lithium bis(trimethylsilyl)-amide afforded (+)-(4R,5S)- melithiazol F (1), whose spectroscopic data were identical with those of the natural product 1. Moreover, the synthesis of (+)-(4R,5S)-melithiazol I (2), was achieved by the same synthetic strategy as that of (+)-(4R,5S)-melithiazol F (1). The antifungal activity of the synthetic melithiazols F (1) and I (2) against the phytopathogenic fungus, Phytophthora capsici, was evaluated by using a paper disc assay method. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Takayama, Hiroyuki,Kato, Keisuke,Akita, Hiroyuki
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p. 644 - 649
(2007/10/03)
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- Efficient lactam synthesis
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Lactams, libraries of lactams, and an efficient method of synthesizing a lactam, including a γ-lactam, in which an α-diazoacetamide of the general structure (I) is reacted under conditions promoting intramolecular C—H insertion, for example in the presenc
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- Efficient lactam synthesis
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Lactams, libraries of lactams, and an efficient method of synthesizing a lactam, including a γ-lactam, in which an α-diazoacetamide of the general structure (I) is reacted under conditions promoting intramolecular C—H insertion, for example in the presenc
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- Synthesis of primary thioamides from nitriles and hydrogen sulfide catalyzed by anion-exchange resin
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A new method has been developed for converting nitriles into primary thioamides. Treatment of various nitriles (Table 1, entries 1-12) with gaseous hydrogen sulfide in a mixture of methanol-water or ethanol-water and in the presence of anion-exchange resin (Dowex 1X8, SH- form) at room temperature and ambient pressure gave the corresponding thioamides in 25-96% yield.
- Liboska, Radek,Zyka, Daniel,Bobek, Miroslav
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p. 1649 - 1651
(2007/10/03)
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- Tricyclic compounds, their production and use
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A compound of the formula: wherein R1 is H or a substituent; m is 1-3; Ar is an aromatic group which may be substituted; X is a bond or a divalent straight-chain group having 1-6 atoms which may be substituted; Y is —S—, —O—, or —N(R2— (R2 is H or a substituent group), Z is —N= or —C(R3)= (R3 is H or a hydrocarbon group), ring A is a benzene ring; ring B is a 5- to 7-membered ring which may be substituted, or a salt thereof is useful for eliciting a prostaglandin I2 receptor agonistic effect.
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- Histamine H1 receptor ligands. Part I. Novel thiazol-4-ylethanamine derivatives: Synthesis and in vitro pharmacology
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A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14-4.82). Copyright (C) 1999 Elsevier Science S.A.
- Walczynski,Timmerman,Zuiderveld,Zhang,Glinka
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p. 533 - 541
(2007/10/03)
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- A REMARKABLY SIMPLE CONVERSION OF NITRILES TO THIOAMIDES
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Thiolacetic acid and light smoothly convert nitriles to thioamides.
- Gauthier, Jacques Yves,Lebel, Helene
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p. 325 - 326
(2007/10/02)
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- A new thionation reagent: Preparation of primary thioamides from nitriles
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Phosphorus decasulfide reacts with sodium sulfide (1:1 ratio) in tetrahydrofuran at 25°C to afford an in situ reagent 1C (5 eq.) that rapidly converts nitriles into thioamides at 20°C.
- Brillon
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p. 1397 - 1401
(2007/10/02)
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- A new method for converting nitriles into primary thioamides by sodium trimethylsilanethiolate
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A new method was developed for converting nitriles into primary thioamides. Treatment of various nitriles 1 with 1.5-2.5 equivalents of sodium trimethylsilyl sulfide (sodium trimethylsilanethiolate) in 1,3-dimethyl-2-imidazolidinone at 20-35°C for 4-30 hours gave the corresponding thioamides 2 in 27-80% yield.
- Lin,Ku,Shiao
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p. 1219 - 1220
(2007/10/02)
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- Equilibrium acidities of 2-alkylthiazolium cations at the C-2α position
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The properties of the 2-(l-methoxyethyl)-3,4-dimethylthiazolium cation (3) and seven related thiazolium cations have been investigated as models for the behavior of 2-(l-hydroxyethyl)thiamin (1). The equilibrium acidity (pKHA +) of 3 in Me
- Bordwell,Satish,Jordan, Frank,Rios, Carlos B.,Chitong Chung
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p. 792 - 797
(2007/10/02)
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- THE REACTION OF NITRILES WITH O,O-DIALKYL-DITHIOPHOSPHORIC ACIDS
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Nitriles react with dialkyldithiophosphoric acids 2a-c to give a mixture of corresponding thioamides and O,O-dialkyl-N-thioacetyl-phosphoroamidothioates 3a-e.The structure of compounds 3 are elucidated chemically and from electronic spectra.The yield of thioamides are improved from the reaction of nitriles with compound 2b in presence of water.Mechanistic consideration on the formation of the products are discussed.
- Yousif, N. M.
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p. 4599 - 4604
(2007/10/02)
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- Morpholino pyridyl thiazole compound
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2-Benzyl-4-(4-pyridyl)thiazoles and derivatives thereof have been made from converting a benzyl cyanide to the corresponding thioamide followed by condensation with a 4-bromoacetylpyridine. The thiazole derivatives are found to be effective immunoregulant
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- STUDIES ON ORGANOPHOSPHORUS COMPOUNDS PART 55 THE TRANSFORMATION OF NITRILES TO THIOAMIDES WITH O,O-DIALKYLDITHIOPHOSPHORIC ACID
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The reaction between nitriles and O,O-dialkyldithiophosphoric acid (2) under anhydrous conditions produces O,O-diethyl-N-thiobenzoylamidophosphate (5), contrary to literature.When water is present the same reaction gives the corresponding thioamides in reasonable to good yields.Mechanistic considerations and spectral data are presented for the products.
- Shabana, R.,Meyer, H.J.,Lawesson, S.-O.
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p. 297 - 306
(2007/10/02)
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- A New Synthesis of 5-Aryl-2,3-dihydro-3-oxo-2-phenyl-1,2,4-thiadiazoles
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A few 5-aryl-2,3-dihydro-3-oxo-2-phenyl-1,2,4-thiadiazoles (IV) have been synthesised by the oxidative dealkylation and simultaneous ring closure of benzyl N-(phenylaminocarbonyl)arenecarboximidothioates (V) which in turn have been prepared by benzylation of N-(phenylaminocarbonyl)arenethiocarboxamides (III).The title compounds can also be obtained by the cyclodehydrogenation of III.
- Ali, Mohammad Ramzan,Singh, R.,Verma, V. K.
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p. 977 - 978
(2007/10/02)
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- DIPHENYLPHOSPHINODITHIOIC ACID: A REAGENT FOR THE CONVERSION OF NITRILES TO THIOAMIDES
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Diphenylphosphinodithioic acid is a reagent useful for a sequence effecting the hydrolysis of nitriles under mild conditions.
- Benner, Steven A.
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p. 1851 - 1854
(2007/10/02)
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- A convenient method for the selective reduction of amides to amines
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A variety of amides have been selectively reduced to the corresponding amines via conversion to their thioamides and treatment with triethyloxonium tetrafluoroborate followed by sodium borohydride. This procedure is compatible with isolated and conjugated double bonds, esters, intro groups, and sulfonamides.
- Raucher, Stanley,Klein, Peter
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p. 4061 - 4064
(2007/10/02)
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