- 4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors
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In Gram-negative bacteria, the major mechanism of resistance to β-lactam antibiotics is the production of one or several β-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-β-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the μM to sub-μM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.
- Gavara, Laurent,Legru, Alice,Verdirosa, Federica,Sevaille, Laurent,Nauton, Lionel,Corsica, Giuseppina,Mercuri, Paola Sandra,Sannio, Filomena,Feller, Georges,Coulon, Rémi,De Luca, Filomena,Cerboni, Giulia,Tanfoni, Silvia,Chelini, Giulia,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
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supporting information
(2021/06/15)
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- Catalytic hydrogenation of α,β-unsaturated carboxylic acid derivatives using copper(i)/N-heterocyclic carbene complexes
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A simple and air-stable copper(i)/N-heterocyclic carbene complex enables the catalytic hydrogenation of enoates and enamides, hitherto unreactive substrates employing homogeneous copper catalysis and H2 as a terminal reducing agent. This atom economic transformation replaces commonly employed hydrosilanes and can also be carried out in an asymmetric fashion.
- Zimmermann, Birte M.,Kobosil, Sarah C. K.,Teichert, Johannes F.
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supporting information
p. 2293 - 2296
(2019/02/27)
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- Copper(i)-catalysed transfer hydrogenations with ammonia borane
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Highly Z-selective alkyne transfer semihydrogenations and conjugate transfer hydrogenations of enoates can be effected by employing a readily available and air-stable copper(i)/N-heterocyclic carbene (NHC) complex, [IPrCuOH]. As an easy to handle and potentially recyclable H2 source, ammonia borane (H3NBH3) is used.
- Korytiaková, Eva,Thiel, Niklas O.,Pape, Felix,Teichert, Johannes F.
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supporting information
p. 732 - 735
(2017/01/13)
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- New orally active diphenylmethyl-based ester analogues of dihydroartemisinin: Synthesis and antimalarial assessment against multidrug-resistant Plasmodium yoelii nigeriensis in mice
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A new series of ester analogues of artemisinin 8a–f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g–j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a–f were found to be 2–4 folds more active than the antimalarial drugs β-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24?mg/kg?×?4?days as well as 12?mg/kg?×?4?days, respectively. In this model β-arteether provided 100% and 20% protection at 48?mg/kg?×?4?days and 24?mg/kg?×?4?days, respectively.
- Chaudhary, Sandeep,Naikade, Niraj K.,Tiwari, Mohit K.,Yadav, Lalit,Shyamlal, Bharti Rajesh K.,Puri, Sunil K.
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p. 1536 - 1541
(2016/07/27)
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- One-pot tandem hydrophenylation and ionic hydrogenation of 3-phenylpropynoic acid derivatives under superelectrophilic activation
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The reactions of esters and amides of 3-phenylpropynoic acid with strong Lewis acids AlX3 (X = Cl, Br) or conjugate Br?nsted-Lewis superacids HX-AlX3 (X = Cl, Br) in benzene and cyclohexane at room temperature afforded 3,3-diphenylpropanoic acid derivatives in up to 94% yield. This tandem reaction of the acetylene bond proceeded by hydrophenylation followed by ionic hydrogenation.
- Nilov, Denis I.,Vasilyev, Aleksander V.
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p. 5714 - 5717
(2015/09/29)
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- Ligand-free nickel-catalysed 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds
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A simple and efficient ligand-free nickel-based catalytic system has been developed for the 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds. With catalyst loadings of 1-2 mol%, a series of 1,4-adducts from chalcones and cinnamates was obtained in moderate to excellent yields within 5-30 min under a nitrogen atmosphere and microwave irradiation. The 1,4-addition of arylboronic acids to acrylates is less efficient.
- Chen, Wen,Sun, Lu,Huang, Xi,Wang, Jiayi,Peng, Yanqing,Song, Gonghua
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p. 1474 - 1482
(2015/05/19)
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- Acid catalyzed rearrangement of vinyl and ketene acetals
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Substituted vinyl and ketene acetals undergo smooth oxygen-to-carbon rearrangement with a catalytic amount of TMSOTf to afford chain-extended ketones or esters, respectively. The developed procedure has been applied to the stereoselective synthesis of C-glycosides from the corresponding anomeric vinyl ethers.
- Maziarz, Elzbieta,Furman, Bart?omiej
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p. 1651 - 1658
(2014/02/14)
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- Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism
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A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.
- Wehn, Paul M.,Harrington, Paul E.,Carlson, Timothy J.,Davis, James,Deprez, Pierre,Fotsch, Christopher H.,Grillo, Mark P.,Lu, Jenny Ying-Lin,Morony, Sean,Pattabiraman, Kanaka,Poon, Steve F.,Reagan, Jeff D.,St. Jean Jr., David J.,Temal, Taoues,Wang, Minghan,Yang, Yuhua,Henley III, Charles,Lively, Sarah E.
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p. 6625 - 6628
(2014/01/06)
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- Rhodium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzooxasilines via enantioselective transmetalation
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A rhodium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzooxasilines has been developed. High enantioselectivities have been achieved by employing (S,S)-Me-Duphos as the ligand through " enantioselective transmetalation".
- Shintani, Ryo,MacIver, Eleanor E.,Tamakuni, Fumiko,Hayashi, Tamio
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supporting information
p. 16955 - 16958,4
(2012/12/13)
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- Rhodium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzooxasilines via enantioselective transmetalation
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A rhodium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzooxasilines has been developed. High enantioselectivities have been achieved by employing (S,S)-Me-Duphos as the ligand through " enantioselective transmetalation".
- Shintani, Ryo,MacIver, Eleanor E.,Tamakuni, Fumiko,Hayashi, Tamio
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supporting information
p. 16955 - 16958
(2013/01/15)
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- New Pd(II) binuclear complexes as effective catalysts in oxidative-heck reaction using arylboronic acid derivatives
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A series of new binuclear Pd(II) complexes based on chelating diimines and bridging diphosphine or diimine ligands have been synthesized and characterized successfully. The formula of the new complexes are [Pd2(mbyp) 2(DPA)2](PF6)4 (1), [Pd 2(mbyp)2(DPE)2] (PF6)4 (2), [Pd2(mbyp)2(4,4-byp)2] (PF 6)4 (3), [Pd2(mbyp)2(t-pye) 2] (PF6)4 (4) [mbyp= 4,4-dimethyl-2,2- bipyridine, DPA= 1,2-bis(diphenylphosphino)acetylene, DPE= 1,2- bis(diphenylphosphino)ethylene, 4,4-byp= 4,4-bipyridine, and t-ype= trans 1,2-bis(4-pyridyl)ethylene)]. The catalytic activities of the new complexes have been investigated in the coupling of arylboronic acid derivatives to various olefins. Results obtained showed interesting catalytic activities and chemoselectivities for the new complexes in the coupling reactions to produce the conjugate addition and heck coupling products under free base or oxidant conditions.
- Suleiman, Rami,Shakil Hussain,Fettouhi, Mohammed,El Ali, Bassam
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scheme or table
p. 850 - 856
(2012/09/22)
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- Palladium-catalyzed desulfitative conjugate addition of aryl sulfinic acids and direct ESI-MS for mechanistic studies
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A new and efficient method for palladium(II) catalytic desulfitative conjugate addition of arylsulfinic acids with α,β-unsaturated carbonyl compound has been developed. The key reacting intermediates including aryl Pd(II) sulfinic intermediate, aryl Pd(II), and C=O-Pd complexes were captured by ESI-MS/MS, which provide new experimental evidence for the understanding of addition mechanism.
- Wang, Huifeng,Li, Yaming,Zhang, Rong,Jin, Kun,Zhao, Defeng,Duan, Chunying
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supporting information; experimental part
p. 4849 - 4853
(2012/07/02)
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- Rhodium-catalyzed asymmetric addition of arylboronic acids to β-phthaliminoacrylate esters toward the synthesis of β-amino acids
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(Chemical Equation Presented) Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to β-phthaliminoacrylate esters took place efficiently to give high yields of β-aryl-β-amino acid esters with 96-99% enantioselectivity, which was realized by use of a hydroxorhodium/chiral diene complex. Copyright
- Nishimura, Takahiro,Wang, Jun,Nagaosa, Makoto,Okamoto, Kazuhiro,Shintani, Ryo,Kwong, Fuk-Yee,Yu, Wing-Yiu,Chan, Albert S. C.,Hayashi, Tamio
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supporting information; experimental part
p. 464 - 465
(2010/03/25)
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- Palladium-bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media
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Palladium/bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media was developed with high yields.
- Lin, Shaohui,Lu, Xiyan
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p. 7167 - 7170
(2007/10/03)
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- Pd(II)-bipyridine catalyzed conjugate addition of arylboronic acid to α,β-unsaturated carbonyl compounds
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A Pd(II)-catalyzed conjugate addition of arylboronic acid to α,β-unsaturated ketones, aldehydes, esters, etc. in the presence of 2,2′-bipyridine was developed. A mechanism involving transmetalation, insertion of the carbon-carbon double bond into the C-Pd bond, and protonolysis of the resulting C-Pd bond is proposed. The reaction conditions are mild and the yield is high. The presence of 2,2′-bipyridine is crucial for the reaction to inhibit β-hydride elimination.
- Lu, Xiyan,Lin, Shaohui
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p. 9651 - 9653
(2007/10/03)
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- Silicone as an organosilicon reagent 2. Rhodium-catalyzed conjugate addition of the silicone reagent to α,β-unsaturated carbonyl compounds
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The reaction of poly(phenylmethylsiloxane) with α,β-unsaturated carbonyl compounds in the presence of aqueous K2CO3 and 3 mol% of [Rh(OH)(cod)]2 gives 1,4-conjugate addition product in good yields. Arylchlorosilanes also u
- Koike, Tooru,Du, Xiaoli,Mori, Atsunori,Osakada, Kohtaro
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p. 301 - 303
(2007/10/03)
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- Rhodium-catalyzed conjugated addition of aryllead reagents to α,β-unsaturated carbonyl compounds in air and water
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In the presence of a rhodium catalyst, α,β-unsaturated esters and ketones (1a-f) react with phenyltrimethyllead 2 in aqueous media and under an air atmosphere to give the corresponding conjugated addition products (3a-e) in high yields.
- Ding,Chen,Wang,Li
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p. 1470 - 1472
(2007/10/03)
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- Asymmetric conjugate 1,4-addition of arylboronic acids to α,β-unsaturated esters catalyzed by rhodium(I)/(S)-binap
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Arylboronic acids underwent the conjugate 1,4-addition to α,β-unsaturated esters to give β-aryl esters in high yields in the presence of a rhodium(I) catalyst. The addition of arylboronic acids to isopropyl crotonate resulted in high yields and high enantioselectivity exceeding 90% ee in the presence of 3 mol % of Rh(acac)(C2H4)2 and (S)-binap at 100 °C. The rhodium/(S)-binap complex provided (R)-3-phenylbutanoate in the addition of phenylboronic acid to benzyl crotonate. The effects on the enantioselectivity of chiral phosphine ligands, rhodium precursors, and substituents on α,β-unsaturated esters are discussed, as well as the mechanistic aspect of the catalytic cycle.
- Sakuma, Satoshi,Sakai, Masaaki,Itooka, Ryoh,Miyaura, Noria
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p. 5951 - 5955
(2007/10/03)
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- REACTIONS OF ARYLAZO ARYL SULFONES WITH α,β-UNSATURATED ESTERS AND KETONES CATALYZED BY PALLADIUM(0) COMPLEX
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The palladium(0) catalyzed reactions of arylazo aryl sulfones (1) with α,β-unsaturated esters in benzene give aryl-substituted esters as major products and hydroarylated esters as minor products.The reactions of 1 with acyclic α,β-unsaturated ketones give considerable amounts of hydroarylated ketones and aryl-substituted ketones under similar conditions, whereas the reactions of 1 with cyclic α,β-unsaturated ketones afforded selectively hydroarylated compounds and no formation of aryl-substituted ketones was found.A plausible reaction mechanism is proposed.Key words: Arylazo aryl sulfones; palladium(0) catalyst; arylation; α,β-unsaturated carbonyl compounds; diarylpalladiumII) intermediate; catalytic cycle.
- Kamigata, Nobumasa,Satoh, Akira,Yoshida, Masato
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p. 121 - 130
(2007/10/02)
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- SELECTIVE REDUCTION OF DIARYL OR ARYL ALKYL ALCOHOLS IN THE PRESENCE OF PRIMARY HYDROXYL OR ESTER GROUPS BY ETHERATED BORON TRIFLUORIDE-TRIETHYLSILANE SYSTEM
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Diaryl or alkyl aryl carbinols bearing a second reducible functional group (such as hydroxyl or ester) are selectively deoxygenated in high yields by the action of etherated boron trifluoride and triethyl silane reducing system.
- Orfanopoulos, Michael,Smonou, Ioulia
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p. 833 - 840
(2007/10/02)
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- KINETICS AND MECHANISM OF THE ADDITION OF ALCOHOLS TO KETENES IN DIETHYL ETHER SOLUTION IN THE PRESENCE OF BORON TRIFLUORIDE
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The kinetics are reported of the boron trifluoride-catalysed additions of seven alcohols to dimethylketene in diethyl ether solution at 25 deg C.All the reactions involve the rapid initial formation of 1:1 alcohol-boron trifluoride adduct (formation constant K) which transfer a proton to the ketene in the slow step of the addition.For t-butyl alcohol, ethanol, methanol, phenylmethanol, and 2-chloroethanol the K values are > 1000, 320+/-50, 300+/-50, 80+/-20, and 65+/-15 l/mol, respectively.The more acididc an alcohol the faster is the reaction of its 1:1 boron trifluoride adduct with the ketene.For t-butyl alcohol the relatively slow reaction of its adduct is catalysed by a further molecule of the adduct and by free boron trifluoride.At 25 deg C the spontaneous addition of ethanol to diphenylketene in ether (like that to dimethylketene) is first order in the ketene and third order in the ethanol concentration.In this reaction diphenylketene is ca. 10-fold more reactive than the dimethyl derivative in the concentration range studied.Whereas the addition of boron trifluoride to the solution catalyses the addition of ethanol (and the other alcohols) to dimethylketene to such an extent that the spontaneous addition makes a negligible contribution to the overall rate, with diphenylketene the alcohol-boron trifluoride adduct is relatively so unreactive that added boron trifluoride strongly inhibits the spontaneous addition.The ethanol-boron trifluoride adducts is > 10E4-fold less reactive towards diphenylketene.These results support our previous conclusions concerning additions of acidic species to ketenes.
- Poon, Nai L.,Satchell, Derek P. N.
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p. 1083 - 1088
(2007/10/02)
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- CONJUGATE ADDITION REACTIONS OF SOME MAGNESIUM-BASED ORGANOCUPRATES WITH α-ETHYLENIC CARBONYL COMPOUNDS
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Bromomagnesium diphenylcuprate and the iodomagnesium dimethylcuprate reagent (prepared from 2 RMgX + CuI) react with methyl or ethyl 3-phenyl-propenoate and methyl 2-butenoate to give 25-70percent yileds of the corresponding conjugate addition products.Th
- Rahman, M. T.,Saha, S. L.,Hansson, A.-T.
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