Pyrrolidine Nitrogen Research Articles

Synthesis, structural studies and antimicrobial activity of copper(II) complexes derived from 2,4-difluoro-6-(((2-(pyrrolidin-1-yl)ethyl)imino)methyl)phenol

Reaction of the Schiff base 2,4-difluoro-6-(((2-(pyrrolidin-1-yl)ethyl)imino)methyl)phenol (HL) with copper salts and some bridging ligands afforded five complexes, [CuClL] (1), [Cu(μ-Br)L]n (2), [Cu(μ-Br)(μ1,5-dca)L]n·nCH3OH (3), [Cu(μ1,3,5-dca)L]n (4) and [Cu(μ1,3-N3)L]n (5) (dca = dicyanoamide). These complexes have been analyzed and characterized by the means of elemental analysis, infrared and electronic spectra, as well as single crystal X-ray diffraction. The Cu atom in the mononuclear complex 1 is in square planar coordination, in the bromido-bridged polynuclear complex 2 is in square pyramidal coordination, in the bromido and dca co-bridged polynuclear complex 3 is in square pyramidal coordination, in the dca bridged polynuclear complex 4 is in octahedral coordination, and in the azido bridged polynuclear complex 5 is in square pyramidal coordination. The Schiff base ligand coordinates to the CuII ions through the phenolate oxygen, imine nitrogen and pyrrolidine nitrogen atoms. The biological study revealed that the complexes have good antimicrobial activity against the bacteria strains B. subtilis, S. aureus, E. coli and P. fluorescens.

Syntheses, Crystal Structures and Antimicrobial Activity of Copper(II) Complexes with the Ligand N,N'-Bis(4-bromosalicylidene)propane-1,2-diamine.

Three new copper(II) complexes, [CuClL] (1), [CuBrL]n (2) and [CuL(NCS)]n (3), derived from the Schiff base 2,4-dichloro-6-((2-pyrrolidin-1-ylethylimino)methyl)phenol (HL) have been prepared and characterized by spectroscopy methods, as well as single crystal X-ray determination. The Cu atom in complex 1 is in square planar coordination, and those in complexes 2 and 3 are in square pyramidal coordination. The Schiff base ligand coordinates to the Cu atoms through phenolate oxygen, imino nitrogen and pyrrolidine nitrogen. The antibacterial activities of the Schiff base and the three copper complexes have been assayed on the bacteria Staphylococcus aureus and Escherichia coli, and the yeast Candida parapsilosis.

Design and Synthesis of D3R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies.

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound. The effect of the flexible linker ((R,S)-trans-2a-d), SBFs ((R,S)-trans-2h-j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP1103.32 of the D3R, thereby reducing the D3R affinity to a suboptimal level.

Synthesis, Crystal Structures and Urease Inhibition of Zinc Complexes Derived from 4-Chloro-2-(((2-(pyrrolidin-1-yl)ethyl)imino)methyl)phenol.

Three new zinc(II) complexes, [Zn3(μ2-η1:η1-OAc)2(μ2-η2:η0-OAc)2L2] (1), [Zn3(μ2-η1:η1-OAc)2(μ1,1-N3)(N3)L2] (2), [Zn2(μ1,3-N3)(N3)(H2O)L2] (3), with the Schiff base ligand 4-chloro-2-(((2-(pyrrolidin-1-yl)ethyl)imino)methyl)phenol (HL) have been synthesized and characterized by elemental analysis, IR and UV-Vis spectroscopic studies. Crystal structures of the complexes were confirmed by single crystal X-ray diffraction. Complex 1 is a bidentate acetato, monoatomic bridging acetato, and phenolato co-bridged trinuclear zinc compound. The Zn atoms are in octahedral and square pyramidal coordination. Complex 2 is a bidentate acetato, end-on azido, and phenolato co-bridged trinuclear zinc compound. The Zn atoms are in trigonal bipyramidal and square pyramidal coordination. Complex 3 is an end-to-end azido bridged dinuclear zinc compound. The Zn atoms are in square pyramidal and trigonal bipyramidal coordination. The Schiff base ligands in the complexes coordinate to the Zn atoms through the phenolate oxygen, imino nitrogen and pyrrolidine nitrogen. The complexes have interesting inhibitory activity on Jack bean urease, with IC50 values of 7.1-15.3 μmol·L-1.

Synthesis and crystal structures of copper, nickel and zinc complexes derived from 2-((2-(pyrrolidin-1-yl)ethylimino)methyl)phenol with antimicrobial activity

Five new copper(II), nickel(II) and zinc(II) complexes, [Cu4Cl2(μ1,1-N3)4(DMF)2] (1), [Cu4Br2(μ1,1-N3)4(DMF)2] (2), [Ni3L2(CH3COO)4]CH3OH (3), [Ni3L2(CH3COO)2(μ1,1-N3)2(CH3OH)2] (4) and [Zn(LH)I2]CH3OH (5), were designed and successfully synthesized using the Schiff base ligand 2-((2-(pyrrolidin-1-yl)ethylimino)methyl)phenol (HL). All the synthesized complexes were characterized using different physico-chemical and spectroscopic methods, like elemental analysis, infrared spectra and single crystal X-ray diffraction. The X-ray structural analysis showed that the Cu atoms in the tetranuclear complexes 1 and 2 are in a square pyramidal coordination, the Ni atoms in the trinuclear complexes 3 and 4 are in an octahedral coordination and the Zn atom in the mononuclear complex 5 is in a tetrahedral coordination. The Schiff base ligand was coordinated to the metal atoms through the phenolate oxygen, imino nitrogen and/or pyrrolidine nitrogen atoms. The biological study indicated that the copper and zinc complexes have interesting antimicrobial activity against B. subtilis, S. aureus, E. coli and P. fluorescens, with MIC values of 0.6–2.3 μmol/L.

Bis(oxotremorine) fumarate bis-(fumaric acid).

The title compound, bis-(oxotremorine) fumarate bis-(fumaric acid) {systematic name: 1-[4-(2-oxopyrrolidin-1-yl)but-2-yn-yl]pyrrolidinium (2E)-but-2-ene-di-o-ate bis-[(2E)-but-2-enedioic acid]}, 2C12H19N2O+·C4H2O4 2-·2C4H4O4, has a single oxotremorine monocation protonated at the pyrrolidine nitro-gen, one fumaric acid mol-ecule and half of a fumarate dianion in the asymmetric unit. The ions and fumaric acid mol-ecules are held together by N-H⋯O and O-H-⋯O hydrogen bonds in 40-membered rings with graph-set notation R 6 6(40). The fumarate ions join these rings into infinite chains along [001].

Facile entry into the 1H-pyrrolo[3,4-b]indolizine-1,3(2H)-dione scaffold via intramolecular Rh(II) carbene trapping

An unusual reactivity of Rh(II) carbenes generated from (E)-3-(2-pyridylmethylene)-4-diazopyrrolidine-2,5-diones was discovered which led to a novel type of fluorescent annelated indolizines (X-ray confirmed structure). The reaction was found to be insensitive to substitution pattern at pyrrolidine nitrogen atom and delivered a series of nine novel indolizines in 74–94% yields. Photophysical properties of obtained indolizines were investigated, which proved them to be blue or green luminophores with absolute quantum yields up to 13.8%. The latter strongly depended on substitution pattern at pyrrolidine nitrogen atom.

Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D2/D3 Receptor Bitopic Ligands.

The crystal structure of the dopamine D3 receptor (D3R) in complex with eticlopride inspired the design of bitopic ligands that explored (1) N-alkylation of the eticlopride's pyrrolidine ring, (2) shifting of the position of the pyrrolidine nitrogen, (3) expansion of the pyrrolidine ring system, and (4) incorporation of O-alkylations at the 4-position. Structure activity relationships (SAR) revealed that moving the N- or expanding the pyrrolidine ring was detrimental to D2R/D3R binding affinities. Small pyrrolidine N-alkyl groups were poorly tolerated, but the addition of a linker and secondary pharmacophore (SP) improved affinities. Moreover, O-alkylated analogues showed higher binding affinities compared to analogously N-alkylated compounds, e.g., O-alkylated 33 (D3R, 0.436 nM and D2R, 1.77 nM) vs the N-alkylated 11 (D3R, 6.97 nM and D2R, 25.3 nM). All lead molecules were functional D2R/D3R antagonists. Molecular models confirmed that 4-position modifications would be well-tolerated for future D2R/D3R bioconjugate tools that require long linkers and or sterically bulky groups.

In vitro affinity for nicotine of soft contact lenses of different materials

Smoking is a risk factor for the development of microbial keratitis and corneal infiltrates in contact lens (CL) wearers. It is still unknown if this risk is directly associated with the presence of nicotine in the eye and if adherence of nicotine on the CL can enhance these effects. A better understanding of the interaction between nicotine and CL materials could offer insights to explain this risk associated with smoking. The aim of this work was to compare the affinity of nicotine to different soft CL materials. CLs from FDA groups I, II, IV, and V were incubated in a 2-mM nicotine solution for 24 h and then in a 0.9% saline solution for the next 24 h. The amount of absorbed and released nicotine per CL was deduced as a function of time (t) by ultraviolet (UV) spectrophotometry and normalised to the mass of the hydrated CL. The data were described by the equation y = b –a t−1, where a and b are constants, and b represents the mass reached at the plateau after ~ 10 min of exposure. Groups IV and V displayed the highest (0.80 ± 0.09 µg) and lowest (0.27 ± 0.08 µg) nicotine absorption per mg of hydrated CL, respectively. The CL affinity for nicotine could be ascribed to the interaction between the positive charge of nicotine pyrrolidine nitrogen and the negative charges of the CLs, especially for the ionic IV group.

Dual 5-HT6 and D3 Receptor Antagonists in a Group of 1H-Pyrrolo[3,2-c]quinolines with Neuroprotective and Procognitive Activity.

In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT6 and dopamine D3 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (CPPQ), a neutral antagonist of 5-HT6R, as a chemical template for designing dual antagonists of 5-HT6/D3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT6 and D3 receptors. The study identified compound 19 ((S)-1-((3-chlorophenyl)sulfonyl)-N-(1-isobutylpyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine), which was classified as a dual 5-HT6/D3R antagonist (Ki(5-HT6) = 27 nM, Ki(D3) = 7 nM). Compound 19 behaved as a neutral antagonist at Gs signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk5)-dependent neurite growth. In contrast to the well characterized 5-HT6R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into procognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus.

Interfering with bacterial cell-to-cell communication is a promising strategy to combat antimicrobial resistance. The natural product hamamelitannin and several of its analogues have been identified as quorum sensing inhibitors. In this paper the synthesis of pyrrolidine-based analogues of a more lead-like hamamelitannin analogue is reported. A convergent synthetic route based on a key ring-closing metathesis reaction was developed and delivered the pyrrolidine analogue in 17 steps in high yield. Chemoselective derivatization of the pyrrolidine nitrogen atom resulted in 6 more compounds. The synthesized compounds were evaluated in a biofilm model, but were all inactive.

A novel method of nicotine quantification in electronic cigarette liquids and aerosols.

The electronic cigarette (e-cigarette) has emerged as popular electronic nicotine delivery devices (ENDs). However, the general safety and validity of e-cigarettes for nicotine delivery efficacy are still not well understood. This study developed a new method for efficient measurement of nicotine levels in both the liquids (e-liquids) used in e-cigarettes and the aerosols generated from the e-cigarettes. Protonation of the pyrrolidine nitrogen of nicotine molecules by addition of excess hydrochloric acid affords an aminium salt that is readily quantified by Fourier transform ion cyclotron mass spectrometry (FT-ICR-MS). The kinetics of nicotine protonation was studied using 1H NMR spectroscopy. Quantitative analyses of nicotine in commercial e-liquids and in the corresponding derived e-cigarette aerosols were carried out using direct infusion FT-ICR-MS. The 1H NMR study of nicotine protonation revealed a first order reaction and an activation energy of 30.05 kJ mol-1. The nicotine levels measured in the commercial e-liquids were within a wide and highly variable range of -2.94% to +25.20% around the manufacturer's stated values. The results indicated considerable differences between the measured levels and the advertised levels of nicotine in the e-liquids. The nicotine quantity measured in aerosols increased linearly both with nicotine level in e-liquids (same number of puffs) and with number of puffs (same e-liquids). These data show that quality control of e-liquids and use characteristics are major variables in efficacy of nicotine delivery.

A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide.

Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.

From pyrrolidinyl-benzodioxane to pyrrolidinyl-pyridodioxanes, or from unselective antagonism to selective partial agonism at α4β2 nicotinic acetylcholine receptor

Each of the four aromatic –CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as α4β2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at α4β2, α3β4 and α7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the α4β2 affinity of [(S,R)-6], but also greatly improved in selectivity over the α3β4 and α7 subtypes and, most importantly, exhibited a highly selective α4β2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective α4β2 antagonist indicates that the benzodioxane substructure confers affinity for the α4β2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.

Water-soluble polymeric chemosensor for detection of Cu2+ ions with high selectivity and sensitivity

Development of water-soluble chemosensors that are selective and sensitive to Cu2+ ions is of tremendous importance owing to their potential applications in biological systems. In the present work, we report the synthesis of a new water-soluble polymer containing pendant rhodamine units that are capable of highly selective and sensitive detection of Cu2+ ions in aqueous medium. Poly(2-pyrrolidinemethyl acrylate) was prepared using RAFT polymerization technique. The pyrrolidine nitrogen group in the polymer was subjected to Aza-Michael type addition with ethyl acrylate that was followed by covalent linking of rhodamine units to the polymer. This polymer was completely water-soluble and found to be capable of sensing Cu2+ ions in aqueous medium. Cu2+-induced opening of the spirolactam ring of the rhodamine units resulted in rapid and easily noticeable colour change, thus enabling a highly selective detection of Cu2+ in μmol range. The ability of these polymeric systems to detect Cu2+ ions in complete aqueous media has more importance than use of organic solvents to solubilize the polymer as reported previously, and thus opened a new window for application of these systems in the detection of copper ions in biological systems.

In search of diamine analogs of the α,α-diphenyl prolinol privileged chiral organocatalyst. Synthesis of diamine derivatives of α,α-diphenyl-(S)-prolinol and their application as organocatalysts in the asymmetric Michael and Mannich reactions

This paper describes improved reaction conditions for the substitution of the hydroxyl group in (S)-diphenyl(pyrrolidin-2-yl)methanol by the azide group, which was then reduced to the diamine derivative. We examined two protecting groups (N-Bn and N-Boc) on the pyrrolidine nitrogen in order to functionalize the primary amino group into various amide, alkylated amine, sulfonamide, thiourea and triazole derivatives. Notably, carefully controlled conditions were required to generate the desired derivatives from the sterically hindered benzhydrylamine moiety. Unexpectedly, upon removal of the N-protecting group in derivatives containing electrophilic polar double bonds (CS, CO) cyclization took place, affording products such as amidines. The target compounds were evaluated as bifunctional organocatalysts in the asymmetric Michael and Mannich addition reactions. (S)-2-(Azidodiphenylmethyl)pyrrolidine (S)-7 was identified as the most efficient organocatalyst among the various diamine derivatives of α,α-diphenyl-(S)-prolinol prepared in this work.

Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors.

Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers, and determination of absolute configuration via enantioselective synthesis showed that the pharmacological activity resided almost exclusively in the (R)-enantiomer.

Pyrrolidinyl Group as Charge Donor for the Excited State Intramolecular Chargetransferin 3-(4-methoxyphenyl)-1-(4-(pyrrolidin-1-yl) phenyl) Prop-2-en-1-one

The absorption and steady state emission properties of a chemically synthesized chalcone, 3-(4-methoxyphenyl)-1-(4-(pyrrolidin-1-yl) phenyl) prop-2-en-1-one (MPPP) containing asymmetrical donor and acceptor groups has been investigated both experimentally and theoretically. The ground state, MPPP has a significant intramolecular charge transfer (ICT) character and a great sensitivity to the hydrogen bond donating ability of the medium as reflected from the absorption spectra in pure non polar, polar and neutral solvents. On the other hand, its excited singlet state exhibits high ICT characters as manifested by the drastic solvatochromic effects. These results are consistent with the data. The absorption spectra of the compound MPPP undergoes minor changes with increasing polarity of the solvents and the fluorescence spectra experiences a distinct bathochromic shifts in the both position and fluorescence quantum yields, increases reaching a maximum before decrease with increasing the solvent effects. The quantum yields decrease with increase in the solvent polarity. The magnitude of change in the dipole moment was also calculated using Austin Model 1 (AM1). These results suggest that the evidence about the intramolecular charge transfer in the emitting singlet state of this compound. The solvent dependence of quantum yields of MPPP was interpreted on the basis of positive and negative solvatokinetic as well as hydrogen bonding effects. Intramolecular charge (ICT) transfer took place from pyrrolidine nitrogen to α, β unsaturated carbonyl in the ground state.

Flexible and Modular Syntheses of Enantiopure 5-cis-Substituted Prolinamines from l-Pyroglutamic Acid

A wide range (25 examples) of 5-cis-substituted prolinamines is prepared in five to ten steps starting from cheap l -pyroglutamic acid. Three routes, differing mainly in the order of introduction of the substituents at the 5-cis position, the pyrrolidine nitrogen atom, and the exocyclic amino function, are successfully developed.

Pyrrolidine nucleotide analogs with a tunable conformation.

Conformational preferences of the pyrrolidine ring in nucleotide analogs 7–14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle.