- Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening
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Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19F ligand-observed NMR experiments.
- Baulard, Alain R.,Biela, Alexandre,Blaise, Mickael,Bourbiaux, Kevin,Cantrelle, Francois-Xavier,Djaout, Kamel,Flipo, Marion,Frita, Rosangela,Hanoulle, Xavier,Herledan, Adrien,Kremer, Laurent,Leroux, Florence,Moune, Martin,Pintiala, Catalin,Piveteau, Catherine,Tanina, Abdalkarim,Vandeputte, Alexandre,Willand, Nicolas,Déprez, Benoit,Fa?on, Léo,Wintjens, René
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supporting information
(2020/06/05)
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- A Biocatalytic Route to Highly Enantioenriched β-Hydroxydioxinones
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A novel biocatalytic system to access a wide variety of β-hydroxydioxinones from β-ketodioxinones employing commercial engineered ketoreductases has been developed. This practical system provides a remarkably straightforward solution to limitations in acc
- Betori, Rick C.,Miller, Eric R.,Scheidt, Karl A.
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supporting information
p. 1131 - 1137
(2017/04/11)
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- Microwave-assisted regiospecific synthesis of pseudohalohydrin esters
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N-Acylbenzotriazoles react regiospecifically with epoxides under palladium catalysis to give novel -(benzotriazol-1-yl)ethyl esters (52-87%) constituting halohydrin ester surrogates. Georg Thieme Verlag Stuttgart · New York.
- El Khatib, Mirna,Elagawany, Mohamed,Todadze, Ekaterina,Khelashvili, Levan,El-Feky, Said A.,Katritzky, Alan R.
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supporting information; experimental part
p. 1384 - 1388
(2012/07/27)
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- Syntheses and reactivities of non-symmetrical "active ester" bi-dentate cross-linking reagents having a phthalimidoyl and acid chloride, 2-benzothiazole, or 1-benzotriazole group
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We have newly synthesized the non-symmetrical "phthalimidoyl active ester" bi-dentate cross-linking reagents having an acid chloride, 2-benzothiazole, or 1-benzotriazole group (i.e., 9, 15, and 16) on the basis of the reactivity study of the "active ester" model compounds, 11-14, toward the various nucleophiles and examined their reaction selectivity towards the same nucleophiles. Then, we applied for the modification of cholesterol at the more reactive site of the bi-dentate linkers to give 3β-cholesteryl 4-(phthalimidoyloxycarbonyl)butyrate (39), and the subsequent reaction of 39 with several amines, such as benzylamine, 4-chlorobenzylamine, 2-phenylethylamine, l-phenylalanine methyl ester, or diphenylalanine benzyl ester as a protein model of the cholesterol antigen.
- Sheikh, Md. Chanmiya,Takagi, Shunsuke,Sakai, Mebumi,Mori, Tasuya,Hayashi, Naoto,Fujie, Tetsuo,Ono, Shin,Yoshimura, Toshiaki,Morita, Hiroyuki
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supporting information; experimental part
p. 1244 - 1254
(2011/04/15)
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- Mechanistic studies of DCC/HOBt-mediated reaction of 3-phenylpropionic acid with benzyl alcohol and studies on the reactivities of 'active ester' and the related derivatives with nucleophiles
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Despite of the extensive study for peptide synthesis, DCC-mediated esterification is left still unclear. Therefore, DCC- and DCC/HOBt-mediated reactions of 3-phenylpropionic acid (1) with benzyl alcohol were carried out under several mechanistic considerations. Further, in order to determine the reactivities of the so-called 'active esters' compounds changing the substituents bearing carbonyl and related derivatives group for the purpose of the development of new class of non-symmetry cross-linkers, we have studied the reaction of model compounds, N-(3-phenylpropionyloxy)benzotriazole (6), N-(3-phenylpropionyloxy)phthalimide (7), 3-phenylpropionyloxybenzothiazole (8), and N-(3-phenylpropionyl)benzotriazole (9) with various nucleophiles under similar conditions were carried out for the comparison. It was revealed to exhibit the order of 6>>8>9>7.
- Sheikh, Md. Chanmiya,Takagi, Shunsuke,Yoshimura, Toshiaki,Morita, Hiroyuki
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supporting information; experimental part
p. 7272 - 7278
(2010/10/02)
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- First synthesis of non-symmetrical "phthalimidoyl active ester" bi-dentate cross-linking reagents having an acid chloride, 2-benzothiazole, or 1-benzotriazol group
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For the purpose of modification of a variety of derivatives, including biologically important compounds, such as sugar derivatives and proteins etc., we have first synthesized several non-symmetrical bi-dentate cross-linking reagents, namely 3-(phthalimidoyloxycarbonyl)butyric acid chloride (1), 4-(2-benzothiazolyloxycarbonyl)butyric-N-hydroxyphthalimide ester (4) and 4-(1-benzotriazoleoxa)butyric-N-hydroxyphthalimide ester (5).
- Sheikh, Md. Chanmiya,Takagi, Shunsuke,Sakai, Mebumi,Abe, Hitoshi,Morita, Hiroyuki
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supporting information; experimental part
p. 4505 - 4508
(2009/03/12)
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- Efficient microwave access to polysubstituted amidines from imidoylbenzotriazoles
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Microwave reactions of primary and secondary amines with imidoylbenzotriazoles 6a-w gave diversely substituted amidines 7a-Aa in 76-94% yields. Convenient preparations of a variety of amides 5a-Ab (87-96%) and imidoylbenzotriazoles 6a-w (56-95%) have also been developed using microwave irradiation under mild conditions and short reaction times. These results demonstrate further the advantages of microwave synthesis and introduce a new application of imidoylbenzotriazoles in the preparation of polysubstituted amidines.
- Katritzky, Alan R.,Cai, Chunming,Singh, Sandeep K.
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p. 3375 - 3380
(2007/10/03)
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- N-acylbenzotriazoles: Neutral acylating reagents for the preparation of primary, secondary, and tertiary amides
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Readily available N-acylbenzotriazoles 2a-q efficiently acylate aqueous ammonia and primary and secondary amines to give primary, secondary, and tertiary amides in good to excellent yields. The wide applicability of the procedure is illustrated by the preparation of (i) α-hydroxyamides from α-hydroxy acids and of (ii) perfluoroalkylated amides.
- Katritzky,He,Suzuki
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p. 8210 - 8213
(2007/10/03)
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- Syntheses of β-lactones, 6: One-step synthesis of β-lactones by aldolization of ketones or aldehydes with 1-acylbenzotriazoles
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Benzotriazolides 1 of alkanoic acids with one hydrogen atom in α-position to the carboxamide group can be deprotonated with lithium diisopropylamide or lithium hexamethyldisilazanide to amide enolates 2 which condense at -90 to -95°C with ketones or aldehydes 3 to afford benzotriazolides of O-lithiated β-hydroxylalkanoic acids 4. These reactive carboxamide derivatives cyclize with elimination of lithium benzotriazolide to the corresponding di- and trisubstituted β-lactones. With regard to the formation of β-monosubstituted β-lactones from aldehydes the use of benzotriazolides as active carboxylic acid derivatives proved to be superior to the application of the corresponding phenyl esters. An α-unsubstituted β-lactone 6 was obtained from 1-acetylbenzotriazole only with cyclohexanone. The other carbonyl compounds 3 did not provide the corresponding α-unsubstituted β-lactones 6. VCH Verlagsgesellschaft mbH, 1996.
- Wedler, Christine,Kleiner, Katharina,Kunath, Annamarie,Schick, Hans
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p. 881 - 885
(2007/10/03)
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