Browsing by Subject "Amides"

Now showing 1 - 4 of 4
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    Chimeric derivatives of functionalized amino acids and α-aminoamides: compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels
    (Elsevier, 2015-07-01) Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T.; Cummins, Theodore R.; Khanna, Rajesh; Kohn, Harold; Department of Psychiatry, IU School of Medicine
    Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4'-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4'-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI=TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.
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    Photochemical Regioselective C(sp3)-H Amination of Amides Using N-Haloimides
    (American Chemical Society, 2021) Pan, Lei; Elmasry, Joseph; Osccorima, Tomas; Cooke, Maria Victoria; Laulhé, Sébastien; Chemistry and Chemical Biology, School of Science
    A metal-free regioselective C(sp3)-H amination of amides using N-haloimides in the presence of lithium tert-butoxide and visible light is presented herein. This photoexcited approach is straightforward, and it aminates a wide variety of amides under mild conditions without the use of photocatalysts, external radical initiators, or oxidants. A halogen-bonded intermediate between the tert-butoxide base and the N-haloimide is proposed to be responsible for the increased photoreactivity. Calculations show that the formation of this electron donor-acceptor complex presents an exergonic energy profile.
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    Photoinduced C(sp3)-H Chalcogenation of Amide Derivatives and Ethers via Ligand-to-Metal Charge-Transfer
    (American Chemical Society, 2022) Niu, Ben; Sachidanandan, Krishnakumar; Cooke, Maria Victoria; Casey, Taylor E.; Laulhé, Sébastien; Chemistry and Chemical Biology, School of Science
    A photoinduced, iron(III) chloride-catalyzed C-H activation of N-methyl amides and ethers leads to the formation of C-S and C-Se bonds via a ligand-to-metal charge transfer (LMCT) process. This methodology converts secondary and tertiary amides, sulfonamides, and carbamates into the corresponding amido-N,S-acetal derivatives in good yields. Mechanistic work revealed that this transformation proceeds through a hydrogen atom transfer (HAT) involving chlorine radical intermediates.
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    Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides
    (American Chemical Society, 2014-04-04) Samaritoni, J. Geno; Copes, Alexus T.; Crews, DeMarcus K.; Glos, Courtney; Thompson, Andre L.; Wilson, Corydon; O’Donnell, Martin J.; Scott, William L.; Department of Chemistry & Chemical Biology, School of Science
    Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R2CO, four bonds away from the site of hydrolysis. Electron-rich acyl R2 groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent’s Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.