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The Journal of Organic Chemistry Feb 2020Decarboxylative A-coupling of -hydroxybenzaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed...
Decarboxylative A-coupling of -hydroxybenzaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed methodology provided a waste-free method for the synthesis of hydroxylated propargylamines which are versatile precursors for various bioactive heterocyclic scaffolds. The experimental and density functional theory studies revealed that the in situ-formed -quinonoid intermediate (formed from -hydroxybenzaldehyde and amine) undergoes a concerted Eschweiler-Clarke type decarboxylation with alkynoic acids. The synthesized compounds were evaluated for MAO-A, MAO-B, and AChE inhibitory activities as potential drug candidates for the treatment of various neurological disorders. Compound was found to be the most potent and selective MAO-B (high selectivity over MAO-A) and AChE inhibitor in the series with IC values of 4.27 ± 0.07 and 0.79 ± 0.03 μM, respectively.
Topics: Monoamine Oxidase Inhibitors; Pargyline; Propylamines; Solvents; Structure-Activity Relationship
PubMed: 31877044
DOI: 10.1021/acs.joc.9b02806 -
Organic Letters Jun 2023Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided...
Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided 9-membered amino-functionalized sulfur-containing heterocycles (dithionine derivatives) in good yields under mild conditions. Propargylamines bearing 5-membered 1,3-dithiolane and 7-membered 1,3-dithiepane rings rearranged in a similar manner yielding 8- and 10-membered -heterocycles, respectively.
Topics: Sulfur; Propylamines; Pargyline; Culture Media
PubMed: 37232086
DOI: 10.1021/acs.orglett.3c01118 -
Molecules (Basel, Switzerland) May 2024A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines,...
A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC values for hMAO-B range from 152.1 to 164.7 nM while the IC values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.
Topics: Alkynes; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pargyline; Propylamines; Structure-Activity Relationship; Molecular Structure
PubMed: 38893361
DOI: 10.3390/molecules29112486 -
The Journal of Organic Chemistry Mar 2021A novel and versatile approach to construct 12-phenacyl-11-benzo[]xanthene-6,11(12)-dione derivatives through copper-catalyzed cascade reaction of propargylamines with...
A novel and versatile approach to construct 12-phenacyl-11-benzo[]xanthene-6,11(12)-dione derivatives through copper-catalyzed cascade reaction of propargylamines with 2-hydroxynaphthalene-1,4-diones has been developed. The procedure is proposed to go through a sequence of 1,4-conjugate addition, intramolecular nucleophilic addition/dehydration, and hydrolysis of alkyne followed by an enol-ketone tautomerization. The reaction provides a new and highly efficient method for the synthesis of 12-phenacyl-11-benzo[]xanthene-6,11(12)-diones by formation of three new bonds and one heterocycle from readily available starting materials in good to high yields (70-88%) with broad functional group compatibility in a single step.
Topics: Catalysis; Copper; Hydrolysis; Naphthols; Pargyline; Propylamines; Xanthenes
PubMed: 33625853
DOI: 10.1021/acs.joc.0c03029 -
Chemical Communications (Cambridge,... Mar 2020We have developed a propargylamine-selective dual fluorescence turn-on system, using ylidenemalononitrile enamines, for post-synthetic DNA labeling, allowing the direct...
We have developed a propargylamine-selective dual fluorescence turn-on system, using ylidenemalononitrile enamines, for post-synthetic DNA labeling, allowing the direct monitoring of DNA using dual emission in living cells.
Topics: Cell Line, Tumor; DNA; Fluorescence; Fluorescent Dyes; Humans; Molecular Structure; Optical Imaging; Pargyline; Propylamines; Staining and Labeling
PubMed: 32068200
DOI: 10.1039/d0cc00255k -
Organic Letters Dec 2019A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is...
A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is described. This method allows the preparation of a series of non-proteinogenic quaternary α-amino acid precursors featuring two contiguous stereogenic centers and a terminal alkyne moiety in high yields with good to excellent diastereo- and enantioselectivities in most cases. The propargylated adducts were elaborated into a diverse set of quaternary α-amino acid derivatives.
Topics: Amino Acids; Catalysis; Copper; Molecular Structure; Pargyline; Stereoisomerism
PubMed: 31820655
DOI: 10.1021/acs.orglett.9b03894 -
The Journal of Organic Chemistry May 2022An interaction of 1,5-diaryl-3-X-pent-4-yn-1-ones (where X stands for piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl) with arylhydrazines proceeds at room...
An interaction of 1,5-diaryl-3-X-pent-4-yn-1-ones (where X stands for piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl) with arylhydrazines proceeds at room temperature and results in 3-aryl-5-arylethynyl-1-phenyl-4,5-dihydro-1-pyrazoles with up to 57-73% yields. Under similar conditions, the cyclocondensation of conjugated 2,4,1-enynones with arylhydrazine proceeds only in the presence of cyclic amines. 1,5-Diaryl-3-X-pent-4-yn-1-ones are reported as synthetic equivalents of conjugated 2,4,1-enynones in reactions with arylhydrazines. On the basis of obtained data, there are highly efficient methods developed for the synthesis of 5-arylethynyl-substituted 4,5-dihydro-1-pyrazoles, as well as for similarly structured 1-pyrazoles prepared by oxidation in AcOH. Presented products possess quite marked fluorescent abilities. Emission maximum wavelengths are located at 453-465 and 363-400 nm, respectively; certain compounds show extremely large Stokes shifts that may reach 91,000 cm.
Topics: Acetylene; Alkynes; Ketones; Pargyline; Propylamines; Pyrazoles
PubMed: 35394780
DOI: 10.1021/acs.joc.2c00198 -
Macromolecular Rapid Communications Mar 2021Multicomponent polymerizations (MCPs) are a group of fascinating polymer synthesis approaches that are developed rapidly in the recent decade. As a popular alkyne-based...
Multicomponent polymerizations (MCPs) are a group of fascinating polymer synthesis approaches that are developed rapidly in the recent decade. As a popular alkyne-based MCP, the A -polycouplings of alkynes, aldehydes, and amines are developed for the synthesis of poly(propargylamine)s under the catalysis of metal catalysts. In this work, through the design of carboxylic acid group-activated alkyne monomers, a catalyst-free, four-component polymerization of propiolic acids, benzylamines, organoboronic acids, and formaldehyde is reported under mild condition at 45 °C in dichloroethane. This four-component polymerization is applicable to different monomer structures, which can afford seven poly(propargylamine)s with up to 94% yields and molecular weights of up to 13 900 g mol . Moreover, the poly(propargylamine)s demonstrate good solubility and processibility, high thermal stability and light refractivity, unique photophysical property, and so on. The simple monomers, mild condition, low cost, high efficiency, and procedure simplicity of this catalyst-free four-component polymerization demonstrates an elegant example of functional polymer synthesis.
Topics: Alkynes; Benzylamines; Catalysis; Formaldehyde; Pargyline; Polymerization; Propylamines
PubMed: 33314555
DOI: 10.1002/marc.202000633 -
Biomacromolecules Feb 2024Both biochemical and mechanical cues could regulate the function of stem cells, but the interaction mechanism of their signaling pathway remains unclear, especially in...
Both biochemical and mechanical cues could regulate the function of stem cells, but the interaction mechanism of their signaling pathway remains unclear, especially in the three-dimensional (3D) culture mode. Higher matrix stiffness promotes osteogenic differentiation of stem cells, and bone morphogenic protein-2 (BMP-2) has been clinically applied to promote bone regeneration. Here, the crosstalk of extracellular mechanical signals on BMP-2 signaling was investigated in rat bone marrow stromal cells (rMSCs) cultured inside cryogels with interconnective pores. Stiff cryogel independently promoted osteogenic differentiation and enhanced the autocrine secretion of BMP-2, thus stimulating increased phosphorylation levels of the Smad1/5/8 complex. BMP-2 mimetic peptide (BMMP) and high cryogel stiffness jointly guided the osteogenic differentiation of rMSCs. Inhibition of rho-associated kinase (ROCK) by Y-27632 or inhibition of nonmuscle myosin II (NM II) by blebbistatin showed that osteogenesis induction by BMP-2 signaling, as well as autocrine secretion of BMP-2 and phosphorylation of the Smad complex, requires the involvement of cytoskeletal tension and ROCK pathway signaling. An interconnective microporous cryogel scaffold promoted rMSC osteogenic differentiation by combining matrix stiffness and BMMP, and it accelerated critical cranial defect repair in the rat model.
Topics: Rats; Animals; Osteogenesis; Cryogels; Gelatin; Cell Differentiation; Mesenchymal Stem Cells; Bone Morphogenetic Protein 2; Bone Marrow Cells; Cells, Cultured; Pargyline
PubMed: 38180887
DOI: 10.1021/acs.biomac.3c01045 -
Pharmaceuticals (Basel, Switzerland) Mar 2020Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical...
Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.
Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.
PubMed: 32151075
DOI: 10.3390/ph13030041