- Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides
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Malaria-causing Plasmodium parasites are developing resistance to antimalarial drugs, providing the impetus for new antiplasmodials. Although pantothenamides show potent antiplasmodial activity, hydrolysis by pantetheinases/vanins present in blood rapidly inactivates them. We herein report the facile synthesis and biological activity of a small library of pantothenamide analogues in which the labile amide group is replaced with a heteroaromatic ring. Several of these analogues display nanomolar antiplasmodial activity against Plasmodium falciparum and/or Plasmodium knowlesi, and are stable in the presence of pantetheinase. Both a known triazole and a novel isoxazole derivative were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although they fail to suppress Plasmodium berghei proliferation in vivo, the pharmacokinetic and contact time data presented provide a benchmark for the compound profile likely required to achieve antiplasmodial activity in mice and should facilitate lead optimization.
- Guan, Jinming,Spry, Christina,Tjhin, Erick T.,Yang, Penghui,Kittikool, Tanakorn,Howieson, Vanessa M.,Ling, Harriet,Starrs, Lora,Duncan, Dustin,Burgio, Gaetan,Saliba, Kevin J.,Auclair, Karine
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p. 4478 - 4497
(2021/05/04)
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- 7-Oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3-Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities
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A solvent-free, green, and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza-sulfone derivatives, namely 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxides through tandem Michael addition–1,3-dipolar cycloaddition of aldoximes was developed. Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine, which upon reaction with divinyl sulfone in a mixer mill affords 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxide derivatives in good overall yields. The newly synthesized bicyclo aza-sulfone derivatives 4 were screened for antibacterial activities. Mostly bicyclo aza-sulfones derived from electron-rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc2155) and those from aliphatic aldehydes the growth of Escherichia coli (DH5α) in moderate to good effect. However, butyraldehyde-derived compound 4r was very effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst- and solvent-free conditions, shorter reaction time, and formation of a new series of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxide derivatives, which are good antibacterial agents against M. smegmatis and E. coli.
- Bhutia, Zigmee T.,Das, Avijit,Biswas, Malabika,Chatterjee, Amrita,Banerjee, Mainak
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p. 506 - 514
(2018/02/09)
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- Poly(ethylene glycol)–bound sulfonyl chloride as an efficient catalyst for transformation of aldoximes to nitriles
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An operationally simple, efficient, and environmentally benign preparation of nitriles in good to excellent yields from various aldoximes in the presence of recyclable poly(ethylene glycol)–bound sulfonyl chloride is described.
- Zhang, Xiao-Lan,Liu, Xiao-Ling,Sang, Xiao-Yan,Sheng, Shou-Ri
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p. 232 - 237
(2017/01/22)
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- Synthesis of 3,5-Disubstituted isoxazoles containing privileged substructures with a diverse display of polar surface area
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We designed and synthesized the molecular framework of 3,5-disubstituted isoxazoles containing privileged substructures with various substituents which uniquely display polar surface area in a diverse manner. A library of 3,5-disubstituted isoxazoles were systematically prepared via 1,3-dipolar cycloaddition of alkynes with nitrile oxides prepared by two complementary synthetic routes; method A utilized a halogenating agent with a base and method B utilized a hypervalent iodine reagent. Through the biological evaluation of corresponding isoxazoles via three independent phenotypic assays, the different pattern of biological activities was shown according to the type of privileged substructure and substituent. These results demonstrated the significance of molecular design via introducing privileged substructures and various substituents to make a diverse arrangement of polar surface area within a similar 3-dimensional molecular framework.
- Kim, Mingi,Hwang, Yoon Soo,Cho, Wansang,Park, Seung Bum
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supporting information
p. 407 - 413
(2017/06/19)
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- Nanocrystalline CeO2 as a Highly Active and Selective Catalyst for the Dehydration of Aldoximes to Nitriles and One-Pot Synthesis of Amides and Esters
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The dehydration of aldoximes into nitriles has been performed in the presence of various metal oxides with different acid-base properties (Al2O3, TiO2, CeO2, MgO). The results showed that a nanocrystalline CeO2 was the most active catalyst. An in situ IR spectroscopy study supports a polar elimination mechanism in the dehydration of aldoxime on metal oxide catalysts, in which Lewis acid sites and basic sites are involved. The Lewis acid sites intervene in the adsorption of the oxime on the catalyst surface while surface base sites are responsible for the C1-H bond cleavage. Thus, the acid-base properties of nanocrystalline CeO2 are responsible for the high catalytic activity and selectivity. A variety of aldoximes including alkyl and cycloalkyl aldoximes have been dehydrated into the corresponding nitriles in good yields (80-97%) using nanosized ceria which moreover resulted in a stable and reusable catalyst. Additionally, it has been showed that a variety of pharmacologically important products such as picolinamide and picolinic acid alkyl ester derivatives can be obtained in good yields from 2-pyridinaldoxime in a one-pot process using the nanoceria as catalyst.
- Rapeyko, Anastasia,Climent, Maria J.,Corma, Avelino,Concepción, Patricia,Iborra, Sara
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p. 4564 - 4575
(2016/07/12)
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- Extending the Scope of the B(C6F5)3-Catalyzed C=N Bond Reduction: Hydrogenation of Oxime Ethers and Hydrazones
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The B(C6F5)3-catalyzed hydrogenation is applied to aldoxime triisopropylsilyl ethers and hydrazones bearing an easily removable phthaloyl protective group. The C=N reduction of aldehyde-derived substrates (oxime ethers and hydrazones) is enabled by using 1,4-dioxane as the solvent known to participate as the Lewis-basic component in FLP-type heterolytic dihydrogen splitting. More basic ketone-derived hydrazones act as Lewis bases themselves in the FLP-type dihydrogen activation and are therefore successfully hydrogenated in nondonating toluene. The difference in reactivity between aldehyde- and ketone-derived substrates is also reflected in the required catalyst loading and dihydrogen pressure.
- Mohr, Jens,Porwal, Digvijay,Chatterjee, Indranil,Oestreich, Martin
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supporting information
p. 17583 - 17586
(2015/12/05)
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- Ac2O/K2CO3/DMSO: An efficient and practical reagent system for the synthesis of nitriles from aldoximes
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The transformation of aldoximes to nitriles using acetic anhydride as dehydration agent under mild reaction conditions is reported. The reaction, which proceeds under weak alkaline condition, allows for the conversion of a range of aldoximes including aromatic aldoximes, alphatic aldoximes, and heterocyclic aldoximes in good to excellent yields. This method has also been successfully applied to the synthesis of calcium channel blocker nilvadipine in pilot scale.
- Song, Yaoping,Shen, Dongguo,Zhang, Qinghua,Chen, Bo,Xu, Guangyu
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p. 639 - 641
(2014/01/23)
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- Highly selective and efficient lewis acid-base catalysts based on lanthanide-containing polyoxometalates for oximation of aldehydes and ketones
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Two lanthanide-containing polyoxometalates (POMs) have been developed as Lewis acid-base catalysts for highly selective and efficient oximation of various aldehydes and ketones under mild conditions. Copyright
- Zhao, Shen,Huang, Lujiang,Song, Yu-Fei
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p. 1659 - 1663
(2013/05/09)
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- One-pot anti-markovnikov hydroamination of unactivated alkenes by hydrozirconation and amination
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A one-pot anti-Markovnikov hydroamination of alkenes is reported. The synthesis of primary and secondary amines from unactivated olefins was accomplished in the presence of a variety of functional groups. Hydrozirconation, followed by amination with nitrogen electrophiles, provides exclusive anti-Markovnikov selectivity. Most products are isolated in high yields without the use of column chromatography.
- Strom, Alexandra E.,Hartwig, John F.
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p. 8909 - 8914
(2013/09/24)
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- Highly selective oximation of aldehydes by reusable heterogeneous sandwich-type polyoxometalate catalyst
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The selectivity of oximation of a variety of aliphatic aldehydes and polycyclic aromatic aldehydes as substrates has been greatly improved by applying a reusable heterogeneous sandwich-type polyoxometalate as catalyst under mild conditions.
- Zhao, Shen,Liu, Lu,Song, Yu-Fei
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supporting information; experimental part
p. 9855 - 9858
(2012/10/08)
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- Ruthenium-catalyzed rearrangement of aldoximes to primary amides in water
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The rearrangement of aldoximes to primary amides has been studied using the readily available arene-ruthenium(II) complex [RuCl2(η 6-C6Me6){P(NMe2)3}] (5 mol %) as catalyst. Reactions proceeded cleanly in pure water at 100 °C without the assistance of any cocatalyst, affording the desired amides in high yields (70-90%) after short reaction times (1-7 h). The process was operative with both aromatic, heteroaromatic, α,β-unsaturated, and aliphatic aldoximes and tolerated several functional groups. Reaction profiles and experiments using 18O-labeled water indicate that two different mechanisms are implicated in these transformations. In both of them, nitrile intermediates are initially formed by dehydration of the aldoximes. These intermediates are then hydrated to the corresponding amides by the action of a second molecule of aldoxime or water. A kinetic analysis of the rearrangement of benzaldoxime to benzamide is also discussed.
- Garcia-Alvarez, Rocio,Diaz-Alvarez, Alba E.,Borge, Javier,Crochet, Pascale,Cadierno, Victorio
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p. 6482 - 6490
(2012/10/30)
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- Efficient microwave-assisted synthesis of oximes from acetohydroxamic acid and carbonyl compounds using BF3·OEt2 as the catalyst
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An efficient synthesis of oximes by reaction of carbonyls with acetohydroxamic acid using BF3·OEt2 as a catalyst is described.
- Sridhar, Madabhushi,Narsaiah, Chinthala,Raveendra, Jillella,Kondal Reddy, Godala,Kishore Kumar Reddy, Mallu,China Ramanaiah, Beeram
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experimental part
p. 4701 - 4704
(2011/09/20)
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- Stereospecific synthesis of syn -α-oximinoamides by a three-component reaction of isocyanides, syn -chlorooximes, and carboxylic acids
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A stereospecific multicomponent reaction among isocyanides, syn-chlorooximes, and carboxylic acids provides an efficient synthesis of biologically relevant syn-α-oximinoamides.
- Pirali, Tracey,Mossetti, Riccardo,Galli, Simona,Tron, Gian Cesare
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supporting information; experimental part
p. 3734 - 3737
(2011/09/15)
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- Catalytic acylation of amines with aldehydes or aldoximes
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The simple nickel salt NiCl2?6H2O catalyzes the coupling of aldoximes with amines to give secondary or tertiary amide products. The aldoxime can be prepared in situ from the corresponding aldehyde. The use of 18O-labeled oximes has allowed insight into the mechanism of this reaction.
- Allen, C. Liana,Davulcu, Simge,Williams, Jonathan M. J.
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supporting information; experimental part
p. 5096 - 5099
(2011/02/21)
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- Electrochemical reductive coupling reactions of aliphatic nitroalkenes
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We describe how to selectively affect either β-to-β coupling (electrohydrodimerization) or coupling between the α and β centers of aliphatic nitroalkenes, the latter in a catalytic process that can be initiated both with and without electrochemistry. Of particular significance is our discovery of conditions that allow electrohydrodimerization to be conducted using aliphatic nitroalkenes bearing acidic protons. Thus, one can affect at will, either a catalytic α-to-β coupling or an electrohydrodimerization using substrates that bear acidic protons, as well as those that do not. We also describe both voltammetric and ESR studies of the simple 1-nitro-3,3-dimethyl-1-butene, as well as the results of quantum mechanical calculations that shed light upon the nature of radial anions derived from electron deficient olefins. Both calculation and experiment suggest that the reluctance of these materials to undergo electrohydrodimerization can be correlated with the low electron density on carbon and the corresponding high value on oxygen, of the radical anion.
- Mikesell, Peter,Schwaebe, Michael,DiMare, Marcello,Little, R. Daniel
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p. 792 - 799
(2007/10/03)
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- Photochemical and Chemical Reduction of Nitroalkenes Using Viologens as an Electron Phase-Transfer Catalyst
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An amphiphilic electron acceptor, i.e., N,N'-dioctyl-4,4'-bipyridinium, was used as an electron carrier between water-oil two phase, in which nitroalkenes in organic phase were readily reduced to the corresponding oximes and/or carbonyl compounds.
- Tomioka, Hideo,Ueda, Koichi,Ohi, Hirofumi,Izawa, Yasuji
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p. 1359 - 1362
(2007/10/02)
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