Search results for "Michael"

A Microscopic Description of SARS-CoV-2 Main Protease Inhibition with Michael Acceptors. Strategies for Improving Inhibitors Design

2020

The irreversible inhibition of the main protease of SARS-CoV-2 by a Michael acceptor known as N3 has been investigated using multiscale methods. The noncovalent enzyme–inhibitor complex was simulated using classical molecular dynamics techniques and the pose of the inhibitor in the active site was compared to that of the natural substrate, a peptide containing the Gln–Ser scissile bond. The formation of the covalent enzyme–inhibitor complex was then simulated using hybrid QM/MM free energy methods. After binding, the reaction mechanism was found to be composed of two steps: (i) the activation of the catalytic dyad (Cys145 and His41) to form an ion pair and (ii) a Michael addition where the …

Design of new sensitive α,β-unsaturated carbonyl 1,8-naphtalimide fluorescent probes for thiol bioimaging

2017

International audience; We report herein an efficient synthesis of news naphtalimide-based fluorescent derivatives functionalized with an a,(3-unsaturated carbonyl group. Probes were synthesized from reaction of an amino-naphtalimide precursor with maleic anhydride. Photophysical study of fluorescent probes and cells labelling were performed, and showed that the reactive derivatives exhibit rich turn on fluorescence properties in presence of different biological thiol (Glutathione and Cysteine) making these systems a very promising way for thiol bioimaging.

Asymmetric synthesis of 3,3′-pyrrolidinyl-dispirooxindoles via a one-pot organocatalytic Mannich/deprotection/aza-Michael sequence

2016

Chemical communications 52, 2249-2252 (2016). doi:10.1039/C5CC10057G

¿El Estado de Derecho en peligro? El juez constitucional contra la Constitución y a favor de la reelección presidencial indefinida : caso Bolivia

2021

In Bolivia, the third term and the habilitation of former President Evo Morales to the 2019 presidential elections was allowed with the acquiescence of the Plurinational Constitutional Court. Despite the fact that the Constitution prohibited it and there was a referendum that rejected indefinite presidential re-election. This occurred through the judicialization of politics that produced a non-formal reform of the Constitution producing a case of abusive constitutionalism and the destabilization of the rule of law.

"What a perverse crew we are" : queer-teoreettinen luenta Michael Cunninghamin romaanista A home at the end of the world

2007

Influence of gamma-aminobutyric acid on baclofen intestinal absorption.

1994

Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by beta-alanine and therefore mediated, at least in part, by the beta-aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a gamma-aminoacid model compound, gamma-aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease a…

Partially competitive inhibition of intestinal baclofen absorption by beta-alanine, a nonessential dietary aminoacid.

1991

In situ intestinal absorption of baclofen in the rat in the presence of beta-alanine has been investigated. Through the perfusion of 0.50 mM baclofen solutions containing variable concentrations of the aminoacid (from 5 to 100 mM), a partially competitive inhibition of baclofen absorption was characterized: absorption rate pseudoconstants of the spasmolytic drug decrease as beta-alanine concentration increases, until a limiting value is obtained (36.8 per cent of that found for baclofen alone). A computer method was developed in order to calculate parameters governing baclofen absorption in the presence of beta-aminoacid, with the following results: Vm = 11.22 mM h-1; Km = 7.42 mM; Ki = 2.4…

Intestinal absorption pathway of gamma-aminobutyric acid in rat small intestine.

1994

Intestinal absorption of gamma-aminobutyric acid (GABA), as a model compound for gamma-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of beta-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They s…

New Fluorinated Peptidomimetics through Tandem Aza-Michael Addition to α-Trifluoromethyl Acrylamide Acceptors: Synthesis and Conformational Study in …

2009

A range of partially modified retro (PMR) psi[NHCH(2)] peptide mimetics containing a hydrolytically stable CH(2)CH(CF(3))CO unit have been synthesized. The first kind of peptidomimetics is obtained from the highly efficient aza-Michael addition of different amines to alpha-trifluoromethyl acrylamide acceptors. Subsequent deprotection of the amino group furnishes the key common intermediate for the synthesis of other families of peptidomimetics: dipeptides, tripeptides, peptidomimetics containing a urea moiety, and structures containing two units of alpha-trifluoromethyl-beta(2)-alanine. Finally, a conformational study of several of the newly synthesized peptidomimetics, performed with the a…

ChemInform Abstract: One-Pot Synthesis of Polysubstituted Indolizines by an Addition/Cycloaromatization Sequence.

2013

Indolizines carrying various substituents in positions 5-8 were obtained from readily available 2-(1H-pyrrol-1-yl)nitriles and α,β-unsaturated ketones or aldehydes in a one-pot procedure. Michael addition of the deprotonated aminonitriles to the acceptors followed by acid-catalyzed electrophilic cyclization produces 5,6-dihydroindolizine-5-carbonitriles. From these stable intermediates, substituted indolizines were obtained via base-induced dehydrocyanation.