63867-69-6Relevant articles and documents
Site-Selective α-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis
Shen, Yangyang,Funez-Ardoiz, Ignacio,Schoenebeck, Franziska,Rovis, Tomislav
supporting information, p. 18952 - 18959 (2021/11/22)
Trialkylamines are widely found in naturally occurring alkaloids, synthetic agrochemicals, biological probes, and especially pharmaceuticals agents and preclinical candidates. Despite the recent breakthrough of catalytic alkylation of dialkylamines, the selective α-C(sp3)-H bond functionalization of widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis, accelerate drug discovery, and execute late-stage pharmaceutical modification with complementary reactivity. However, the canonical methods always result in functionalization at the less-crowded site. Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric control that dominates such processes. By rapidly establishing an equilibrium between α-amino C(sp3)-H bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower radical-trapping step with electron-deficient olefins to selectively forge a C(sp3)-C(sp3) bond with the more-crowded α-amino radical, with the overall selectivity guided by the Curtin-Hammett principle. This subtle reaction profile has unlocked a new strategic concept in direct C-H functionalization arena for forging C-C bonds from a diverse set of trialkylamines with high levels of site selectivity and preparative utility. Simple correlation of site selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon centers and implement late-stage functionalization techniques, hold potential to streamline complex trialkylamine synthesis and accelerate small-molecule drug discovery.
Cyano-containing biquaternary ammonium compound as well as preparation method and application thereof
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Paragraph 0062-0064; 0074-0076, (2021/07/10)
The invention relates to a cyano-containing biquaternary ammonium compound as well as a preparation method and application thereof, and particularly discloses a biquaternary ammonium compound as shown in a formula (I), or a crystal form, a solvate, a stereoisomer, an isotope substitute or a salt thereof. The biquaternary ammonium compound does not contain nitro, so that the potential safety hazard of nitro-containing compounds is effectively avoided; meanwhile, the biquaternary ammonium compound is low in single-time medication dosage and quick in effect taking, can provide a thorough muscle relaxation effect for 2-10 minutes, can realize a super-short-acting non-depolarization muscle relaxation effect only by depending on metabolism of an organism, and quickly and automatically fades after playing the super-short-acting muscle relaxation effect. Therefore, the biquaternary ammonium compound, or the crystal form thereof, or the solvate thereof, or the stereoisomer thereof, or the isotope substitute thereof, or the salt thereof provided by the invention has a very good application prospect in preparation of skeletal muscle relaxation drugs with low dosage, quick effect, quick recovery and small toxic and side effects.
QSAR and molecular docking studies of the inhibitory activity of novel heterocyclic GABA analogues over GABA-AT
Rodríguez-Lozada, Josué,Tovar-Gudi?o, Erika,Guevara-Salazar, Juan Alberto,Razo-Hernández, Rodrigo Said,Santiago, ángel,Pastor, Nina,Fernández-Zertuche, Mario
, (2018/11/24)
We have previously reported the synthesis, in vitro and in silico activities of new GABA analogues as inhibitors of the GABA-AT enzyme from Pseudomonas fluorescens, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds. With the goal of finding more potent inhibitors, we now report the synthesis of a new set of GABA analogues with a broader variation of heterocyclic scaffolds at the γ-position such as thiazolidines, methyl-substituted piperidines, morpholine and thiomorpholine and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These structural modifications led to compound 9b which showed a 73% inhibition against this enzyme. In vivo studies with PTZ-induced seizures on male CD1 mice show that compound 9b has a neuroprotective effect at a 0.50 mmole/kg dose. A QSAR study was carried out to find the molecular descriptors associated with the structural changes in the GABA scaffold to explain their inhibitory activity against GABA-AT. Employing 3D molecular descriptors allowed us to propose the GABA analogues enantiomeric active form. To evaluate the interaction with Pseudomonas fluorescens and human GABA-AT by molecular docking, the constructions of homology models was carried out. From these calculations, 9b showed a strong interaction with both GABA-AT enzymes in agreement with experimental results and the QSAR model, which indicates that bulky ligands tend to be the better inhibitors especially those with a sulfur atom on their structure.
