Ephedrine Derivatives Research Articles

Gold and Biocatalysis for the Stereodivergent Synthesis of Nor(pseudo)ephedrine Derivatives: Cascade Design Toward Amino Alcohols, Diols, and Diamines

AbstractThe combination of gold(I) and enzyme catalysis has provided access to a series of nor(pseudo)ephedrine derivatives in a regio‐ and stereoselective manner. The approach involves developing IPrAuNTf2‐catalyzed hydration of 1‐phenylprop‐2‐yn‐1‐yl acetate orN‐(1‐phenylprop‐2‐yn‐1‐yl)acetamide, followed by (dynamic) asymmetric biotransamination or bioreduction of the corresponding keto ester or keto amide intermediates. Enzyme actions were completely selective towards the modification of the methyl ketones in a highly stereoselective manner, allowing the synthesis of enantio‐ and diastereomerically enriched products using either racemic or optically active starting materials. Thus, a series of amino alcohol, diol, and diamine derivatives were produced from propargyl esters or amides (57 to 86% isolated yield), the biocatalyst of choice determining the (stereo)selectivity of the overall cascade process (70–99% diastereomeric excess and >98% enantiomeric excess), and providing access to nor(pseudo)ephedrine compounds in a straightforward manner.magnified image

Ephedra alata Subsp. Alenda as a Novel Source of Bioactive Phytochemicals: Characterization Based on the Mass Spectrometry and Profiling of Antioxidant and Anti-Inflammatory Properties.

The aim of the present study was to examine, for the first time, the phytochemical content of Ephedra alata pulp extract (EAP) and explore its antioxidant and anti-inflammatory capacities. High-performance liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry (HPLC-ESI-QTOF/MS) was used for phytochemical analysis and three in vitro antioxidant assays together with three in vitro anti-inflammatory tests were used for the assessment of biological activity. The HPLC-ESI-QTOF/MS analysis revealed the presence of 42 metabolites, including flavonoids, sphingolipides, fatty acids, ephedrine derivatives, and amino acid derivatives. In vitro findings revealed that EAP has interesting 2,2-diphenyl-1-picrylhydrazyl (DPPH), superoxide, and ferrous ion chelating capacities (IC50 values were 0.57 mg/mL, 0.55 mg/mL, and 0.51 mg/mL for DPPH, superoxide radical, and ferrous ion, respectively). Furthermore, EAP showed a noticeable anti-inflammatory ability by inhibiting the two cyclooxygenase isoforms, COX-1 and COX-2 (IC50 of 59.1 and 58.8 µg/mL for COX-1 and COX-2, respectively), preventing protein denaturation (IC50 = 0.51 mg/mL), and protecting membrane stabilization (IC50 = 0.53 mg/mL). The results highlighted the use of Ephedra alata pulp as a potential source of natural compounds with therapeutic effects for the management of inflammatory disorders.

Characterization of binding properties of ephedrine derivatives to human alpha-1-acid glycoprotein

Most drugs, especially those with acidic or neutral moieties, are bound to the plasma protein albumin, whereas basic drugs are preferentially bound to human alpha-1-acid glycoprotein (AGP). The protein binding of the long-established drugs ephedrine and pseudoephedrine, which are used in the treatment of hypotension and colds, has so far only been studied with albumin. Since in a previous study a stereoselective binding of ephedrine and pseudoephedrine to serum but not to albumin was observed, the aim of this study was to check whether the enantioselective binding behavior of ephedrine and pseudoephedrine, in addition to the derivatives methylephedrine and norephedrine, is due to AGP and to investigate the influence of their different substituents and steric arrangement. Discontinuous ultrafiltration was used for the determination of protein binding. Characterization of ligand-protein interactions of the drugs was obtained by saturation transfer difference nuclear magnetic resonance spectroscopy. Docking experiments were performed to analyze possible ligand-protein interactions. The more basic the ephedrine derivative is, the higher is the affinity to AGP. There was no significant difference in the binding properties between the individual enantiomers and the diastereomers of ephedrine and pseudoephedrine.

Phytochemical Profiling of Ephedra alata subsp. alenda Seeds by High-Performance Liquid Chromatography—Electrospray Ionization—Quadrupole-Time-of-Flight-Mass Spectrometry (HPLC-ESI-QTOF-MS), Molecular Docking, and Antioxidant, Anti-diabetic, and Acetylcholinesterase Inhibition

The aim of the current work was to study for the first time the phytochemical profile of Ephedra alata subsp. alenda seeds extract (ESS). The extract was characterized using high-performance liquid chromatography coupled to electrospray ionization quadropole time-of-flight mass spectrometry (HPLC–ESI–QTOF/MS). The antioxidant and antihemolytic properties were evaluated, and the inhibitory properties against α-amylase, α-glucosidase, and acetylcholinesterase were assessed. Chromatographic analysis revealed that ESS was rich in bioactive components including ephedrine derivatives, sphingolipides, flavonol, hexoside, and fatty acids. Furthermore, ESS displayed important antioxidant activity and α-glucosidase, α-amylase, and acetylcholinesterase inhibitory capacities. Moreover, ESS showed a preventive effect against oxidative stress induced hemolysis. In silico analysis confirmed the beneficial effects of ESS-phytochemicals. In fact, 3 out of the 14 investigated compounds, including isorhamnetin rutinoside, isoschaftoside, and kaempferol-3-rhamnoside, exhibited the best binding scores (less than −7) with two anti-diabetic targets. Isorhamnetin rutinoside also showed the highest number of hydrogen bonds with acetylcholinesterase highlighting its anti-cholieaterase potency. The current study suggested that seeds from E. alata are interesting sources of bioactive compounds and recommended as enzyme inhibitory agents in food and pharmaceuticals.

Combination of Ephedra sinica stems and Terminalia chebula fruits produces new ephedrine derivatives in vivo that diminish the permeability to BBB while retaining airway dilation and hepatoprotective effects

Ethnopharmacological relevanceThe stems of Ephedra sinica and the fruits of Terminalia chebula are combined using in traditional Mongolian medicine formula “Gurigumu-7” for liver diseases. E. sinica stems contains ephedrine with broncho-dilatory activity. However, ephedrine can pass through the blood-brain barrier (BBB) and excite the central nervous system (CNS) to cause insomnia and restlessness. Aim of the studyThe present study was to investigate the structures and bioactivities of new compounds formed in vivo after co-administration of E. sinica stems and T. chebula fruits. Materials and methodsPharmacokinetic investigation was carried out in rats. A parallel artificial membrane permeability measurement system was used to determine BBB permeability. Ex vivo experiments using tracheal rings of guinea pig was performed to examine the tracheal relaxation effect. In vivo hepatoprotective tests were carried out in Tg (fabp10a: dsRed) liver transgenic zebrafish. The fluorescent probe, 2,7-dichlorodihydrofluorescein diacetate, was used to measure reactive oxygen species, and UHPLC-MS was used to determine glutathione concentrations after derivatization with N-ethylmaleimide. ResultsNew ephedrine derivatives (1 and 2) formed in vivo and reached their maximum serum concentrations at 0.5 h after administration of the two herbal drugs. Compounds 1 and 2 showed lower BBB permeability than ephedrine, suggesting that they have less adverse effects on the CNS. Compounds 1 and 2 relaxed the tracheal rings and had strong hepatoprotective effect on transgenic zebrafish with liver specific expression of RFP. Compounds 1 and 2 significantly reduced the level of reactive oxygen species while increasing that of glutathione in thioacetamide-treated zebrafish, which might be the hepatoprotective mechanism. ConclusionThese results provided evidences that the chemical constituents in various herbal drugs in a medicinal formula can interact to generate new compounds with fewer side effects and increased or additive bioactivity.

Identification and characterization of chemically masked derivatives of pseudoephedrine, ephedrine, methamphetamine, and MDMA.

The emergence of chemically masked illicit drugs represents a challenge to global initiatives that are working to prevent their manufacture and distribution. Targeted analytical techniques currently used by law enforcement to identify unknown materials rely on spectroscopic and spectrophotometric databases that do not currently include some of these compounds, making their identification challenging. This study aimed to update compound spectral libraries to aid in the rapid detection and identification of these masked drugs, as well as to provide insight into their synthetic procedures. Five commonly employed protecting groups, acetyl, p-tosyl, methoxycarbonyl, Fmoc, and t-Boc, were appended to pseudoephedrine, ephedrine, methamphetamine, and MDMA. Characterization was carried out using NMR, GC-MS, FTIR, high-resolution LC-MS/MS, and common screening color tests. Some of the methoxycarbonyl and t-Boc derivatives and all of the Fmoc derivatives showed partial or full thermal degradation or rearrangement during GC-MS analysis, while LC-MS/MS analysis did not always show characteristic fragmentation that would allow unambiguous assignment of the structure. Restricted rotation in some of the derivatives meant that NMR assignments could only be made using NMR spectra acquired at elevated temperature. Therefore, GC-MS and LC-MS/MS analyses serve complementary roles for these derivatives, with NMR providing confirmation of structure for the pure materials if necessary.

A multidisciplinary approach to investigate the osteobiography of the Roman Imperial population from Muracciola Torresina (Palestrina, Rome, Italy)

The present research provides the osteobiographical reconstruction of the Roman Imperial population of the rural area of Muracciola Torresina (Palestrina, Rome, Italy) through an innovative multidisciplinary approach, combining evidence from skeletal biology, biomolecules and archaeobotany.The excavation of the site, unearthed 76 individuals: 84.2% adults and 15.8% non-adults. Morphological examination showed a higher prevalence of females with respect to males (M:F = 0.89). Musculoskeletal stress marker analysis highlighted a probable division of daily tasks between sexes; the observed modifications mainly affected the upper limbs with a particular involvement of shoulder and elbow joints. The population seems to have experienced physically strenuous life conditions, as suggested by the high frequency of degenerative and infectious diseases.Carbon and nitrogen stable isotope data supported an omnivorous diet mainly based on C3 plants and terrestrial animal protein. No statistically significant difference was found between sexes or age classes, even though a discrete variability of nitrogen isotopic values was observed which was hypothesized to reflect the consumption of pulses by certain individuals with the lowest values. Microscopic analysis of dental calculus detected Triticeae starch granules in the majority of the analyzed individuals. Chromatographic profiles additionally revealed the presence of ephedrine derivatives in the calculus of two individuals, an alkaloid which might indicate the consumption of Ephedra species used as medicinal plant due to its bronchodilator, nasal decongestant and vasoconstrictor properties.This use of multiple cutting-edge techniques has revealed a detailed snapshot of the diet and lifeways of the first Roman Imperial population to be recovered from the area of ancient Praeneste.

Ephedrine as a lead compound for the development of new DPP-IV inhibitors.

Extracts from Ephedra species have been reported to be effective as antidiabetics. A previous in silico study predicted that ephedrine and five ephedrine derivatives could contribute to the described antidiabetic effect of Ephedra extracts by inhibiting dipeptidyl peptidase IV (DPP-IV). Finding selective DPP-IV inhibitors is a current therapeutic strategy for Type 2 diabetes mellitus management. Therefore, the main aim of this work is to experimentally determine whether these alkaloids are DPP-IV inhibitors. Materials& methods: The DPP-IV inhibition ofEphedra's alkaloids was determined via a competitive-binding assay. Then, computational analyses were used in order to find out the protein-ligand interactions and to perform a lead optimization. Our results show that all six molecules are DPP-IV inhibitors, with IC50 ranging from 124μM for ephedrine to 28 mM for N-methylpseudoephedrine. Further computational analysis shows how Ephedra's alkaloids could be used as promising lead molecules for designing more potent and selective DPP-IV inhibitors.

Synthesis and Bioactivity of Novel N-Benzylic and N-Phenethylic Ephedrine Derivatives

A range of N-benzylic and N-phenethylic ephedrine derivatives were prepared in a one-pot procedure starting from the two enantiomers of ephedrine using the Potier reagent, and a polyfunctional aryl- or benzylic organozinc halide. The biological activity in indatraline MS Binding Assays addressing hDAT, hNET and hSERT was determined and discussed.

Characterization of complexes between phenethylamine enantiomers and β-cyclodextrin derivatives by capillary electrophoresis-Determination of binding constants and complex mobilities.

To optimize chiral separation conditions and to improve the knowledge of enantioseparation, it is important to know the binding constants K between analytes and cyclodextrins and the electrophoretic mobilities of the temporarily formed analyte-cyclodextrin-complexes. K values for complexes between eight phenethylamine enantiomers, namely ephedrine, pseudoephedrine, methylephedrine and norephedrine, and four different β-cyclodextrin derivatives were determined by affinity capillary electrophoresis. The binding constants were calculated from the electrophoretic mobility values of the phenethylamine enantiomers at increasing concentrations of cyclodextrins in running buffer. Three different linear plotting methods (x-reciprocal, y-reciprocal, double reciprocal) and nonlinear regression were used for the determination of binding constants with β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin and 6-O-α-maltosyl-β-cyclodextrin. The cyclodextrin concentration in a 50 mM phosphate buffer pH 3.0 was varied from 0 to 12 mM. To investigate the influence of the binding constant values on the enantioseparation the observed electrophoretic selectivities were compared with the obtained K values and the calculated enantiomer-cyclodextrin-complex mobilities. The different electrophoretic mobilities of the temporarily formed complexes were crucial factors for the migration order and enantioseparation of ephedrine derivatives. To verify the apparent binding constants determined by capillary electrophoresis, a titration process using ephedrine enantiomers and β-cyclodextrin was carried out. Furthermore, the isothermal titration calorimetry measurements gave information about the thermal properties of the complexes.

Supramolecular chemistry controlled by packing interactions during structure-direction of nanoporous materials: Effect of the addition of methyl groups on ephedrine derivatives

A combined experimental and computational study has been applied in order to understand the effect of the addition of subsequent methyl groups to chiral (1R,2S)-(−)-ephedrine on its structure-directing behavior during crystallization of the nanoporous AFI aluminophosphate. Results show that bare ephedrine and the double-methylated N,N-dimethyl-ephedrinium display the most efficient structure-directing abilities, while the mono-methylated derivative shows a poor structure-directing capacity towards this framework. Fluorescence spectroscopy indicates that confinement of the mono- and di-methylated derivatives within the nanopores of the AFI channels involves a preferential incorporation of the SDA molecules as monomers. In contrast, occlusion of the bare ephedrine can lead to a strong supramolecular aggregation, depending on the synthesis conditions. Molecular simulations suggest that the stronger trend of ephedrine to form supramolecular aggregates when confined within the AFI channels is due to the formation of two intermolecular H-bonds between consecutive molecules in the dimers interface, which balances the strong electrostatic repulsion between closely-located positive charges of the N atoms under this supramolecular arrangement. The addition of subsequent methyl groups reduces the possibility of establishing these interdimer H-bond interactions that stabilize dimers while provoking steric repulsions, thus reducing the supramolecular aggregation.

On the possibility of ephedrine detection: time-resolved fluorescence resonance energy transfer (FRET)-based approach.

Ephedrine is one of the main precursor compounds used in the illegal production of amphetamines and related drugs. Actually, conventional analytical methods such as high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), and gas chromatography-mass spectrometry (GC-MS) are used for the detection of ephedrine; sadly, these methods require qualified personnel and are time-consuming and expensive. In order to overcome these problems, in recent years, different methods have been developed based on the surface plasmon resonance (SPR) and electrochemical method. In this work, we present a simple, rapid, and effective method to detect the presence of ephedrine in solution, based on competitive fluorescence resonance energy transfer (FRET) assay. The antibody anti-ephedrine and ephedrine derivative were produced and labeled respectively, with two different fluorescent probes (donor and acceptor). The change in FRET signal intensity between donor and acceptor ephedrine compounds gives the possibility of detecting ephedrine tracesof at least 0.81 ± 0.04ppm (LOD). Graphical abstract A new Time-resolved Fluorescence Resonance Energy Transfer (FRET) assay for ephedrine detection.

Body image and eating disorders are common in professional and amateur athletes using performance and image-enhancing drugs (pieds). A cross-sectional study

IntroductionThe use of Performance and Image-Enhancing Drugs (PIEDs) is on the increase and appears to be associated with several psychopathological disorders, whose prevalence in unclear.Objectives/AimsWe aimed to evaluate the differences–if any–in the prevalence of body image disorders (BIDs) and eating disorders (EDs) in PIEDs users athletes vs. PIEDs nonusers ones.MethodsWe enrolled 84 consecutive professional and amateur athletes (35.8% females; age range = 18–50), training in several sports centers in Italy. They underwent structured interviews (SCID I/SCID II) and completed the Body Image Concern Inventory (BICI) and the Sick, Control, One, Fat, Food Eating Disorder Screening Test (SCOFF). Mann-Whitney U test and Fisher's exact test were used for comparisons.ResultsOf the 84 athletes, 18 (21.4%) used PIEDs. The most common PIEDs were anabolic androgenic steroids, amphetamine-like substances, cathinones, ephedrine, and caffeine derivatives (e.g. guarana). The two groups did not differ in socio-demographic characteristics, but differed in anamnestic and psychopathological ones, with PIEDs users athletes being characterized by significantly (P-values < 0.05) higher physical activity levels, consuming more coffee, cigarettes, and psychotropic medications (e.g. benzodiazepines) per day, presenting more SCID diagnoses of psychiatric disorders, especially Substance Use Disorders, Eating Disorders, Body Dysmorphic Disorder (BDD), and General Anxiety Disorders, showing higher BICI scores, which indicate a higher risk of BDD, and higher SCOFF scores, which suggest a higher risk of BIDs and EDs.ConclusionsIn PIEDs users athletes body image and eating disorders, and more in general psychopathological disorders, are more common than in PIEDs nonusers athletes.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Preparation of tertiary amines by the reaction of iminium ions derived from unsymmetrical aminals with zinc and magnesium organometallics.

We report a convenient one-pot preparation of polyfunctional tertiary amines, including various biorelevant phenethylamines or ephedrine derivatives, via the reaction of new functionalized iminium ions with a variety of zinc and magnesium organometallic reagents. These iminium ions were generated from unsymmetrical aminals, obtained by the in situ addition of various amides to Tietze's iminium salt [Me2NCH2(+)CF3COO(-)]. A functionalized aniline, prepared by this method, was converted to a quinolidine via an intramolecular Heck reaction.

A cocrystal of two MoVIcomplexes bearing different diastereomers of the 2,4-di-tert-butyl-6-{[(1-oxido-1-phenylpropan-2-yl)(methyl)amino]methyl}phenolate ligand derived from (+)-ephedrine

The title cocrystal contains two chiral conformational diastereomers, viz. (1S,2R,RN)- and (1S,2R,SN)-, of [2,4-di-tert-butyl-6-{[(1-oxido-1-phenylpropan-2-yl)(methyl)amino]methyl}phenolato](methanol)-cis-dioxidomolybdenum(VI), [Mo(C25H35NO2)O2(CH3OH)], representing the first example of a structurally characterized molybdenum complex with enantiomerically pure ephedrine derivative ligands. The Mo(VI) cations exhibit differently distorted octahedral coordination environments, with two oxide ligands positioned cis to each other. The remainder of the coordination comprises phenoxide, alkoxide and methanol O atoms, with an amine N atom completing the octahedron. The distinct complexes are linked by strong intermolecular O-H···O hydrogen bonds, resulting in one-dimensional molecular chains. Furthermore, the phenyl rings are involved in weak T-shaped/edge-to-face π-π interactions with each other.

A surface plasmon resonance-based biochip to reveal traces of ephedrine

Ephedrine is a crucial chemical precursor for clandestinely produced amphetamine and its related drugs. Also, ephedrine is intentionally added to illegal preparations of methamphetamine or amphetamine because it is cheaper than the other two drugs. Consequently there is a pressing need to prevent the entry of ephedrine into commerce. Therefore the challenge calls for non-invasive techniques that provide data on the presence of ephedrine even in trace amounts. In this paper we describe the synthesis of a new ephedrine derivative with a carbon linker featuring an amino reactive group, and its conjugation to the glutamine binding protein (GlnBP) from E. coli as a carrier protein for the production of polyclonal antibodies against ephedrine. Proof-of-principle results of an efficient SPR-based indirect competitive immunoassay for the detection and quantification of ephedrine are presented. The detection limit of the assay was about 33 ng ml−1.

Intramolecular N→Sn Coordination in Tin(II) and Tin(IV) Compounds Based on Enantiopure Ephedrine Derivatives

The syntheses and molecular structures of the intramolecularly coordinated tin(II) compounds {CH(2)N(Me)CH(Me)CH(Ph)O}(2)SnL (2, L = lone pair; 4, L = W(CO)(5); 5, L = Cr(CO)(5)) and of the related hydroxido-substituted tin(IV) compound [{CH(2)N(Me)CH(Me)CH(Ph)O}(2)Sn(OH)](2)O, 6a, are reported. Also reported are the molecular structures of the enantiopure N,N'-ethylenebis-(1R,2S)-ephedrine, {CH(2)N(Me)CH(Me)CH(Ph)OH}(2) (1), and its hydrobromide {CH(2)N(Me)CH(Me)CH(Ph)OH}(2)·HBr (1a).

Syntheses, Structures and Reactivity of New Intramolecularly Coordinated Tin Alkoxides Based on an Enantiopure Ephedrine Derivative

AbstractThe syntheses of the tin compounds [LSn]2 (2), spiro‐L2Sn (3), [LSnW(CO)5]2 (4), [LSnBr2]2 (5), spiro‐L2Sn·SnBr4 (6) and LSn[OC(O)Ph]2 (8), where L = MeN(CH2CMe2O)[(S)‐CH(Me)‐(R)‐CH(Ph)O], and (Ph4P)2SnBr6 (7) are reported. The compounds were characterized by elemental analysis, multinuclear NMR spectroscopy including 119Sn cross polarisation–magic angle spinning NMR (CP–MAS) (2, 3–6), electrospray ionization mass spectrometry (2–4) and single crystal X‐ray diffraction analysis (2, 2·C7H8, 3a, 3b, 4·C7H8, 5, 6·C7H8, 7).

ChemInform Abstract: Pd(II)‐Catalyzed o‐C—H Acetoxylation of Phenylalanine and Ephedrine Derivatives with MeCOOOtBu/Ac2O.

AbstractA new protocol is applied to various triflamide substrates tolerating a broad spectrum of functional groups.

ChemInform Abstract: Enantioselective Reaction of Diethylzinc with Arenecarbaldehydes in the Presence of Ephedrine Derivatives.

ChemInform Abstract: Enantioselective Reaction of Diethylzinc with Arenecarbaldehydes in the Presence of Ephedrine Derivatives.