Antiplasmodial Drugs in the Gas Phase: A CID and DFT Study of Quinolon-4(1H)-Imine Derivatives

The gas-phase behavior of 12 quinolon-4(1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold. Figure

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Preparation and structures of some new 1H-pyrazole derivatives

Some new 3,5-diaryl-1H-pyrazoles were prepared from aryl methyl ketones via Claisen condensation with aromatic esters and followed by cyclization with hydrazine monohydrate. Their structures were confirmed by IR, ¹H NMR spectroscopy, mass spectrometry and elemental analysis. The X-ray structure for 3(5)-(4-tert-butylphenyl)-5(3)-(4-methoxyphenyl)-1H-pyrazole (2b) was presented. The results show that compound 2b exists as tautomers I and II, and its molecules are connected by the N–H···N intermolecular hydrogen bonds to form cyclic dimers consisting of the tautomers I and II.     

A facile synthesis of fused spiroketal skeleton: 2,2′-spirobi(4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydrochroman)

A one-pot synthesis of fused spiroketal skeleton, 2,2′-spirobi(4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydrochroman) 4a-c, has been achieved for the first time by an application of Michael reaction between dimedone (5,5-dimethylcyclohexan-1,3-dione) 1 and trans,trans-diarylideneacetone (1,5-diaryl-1,4-pentadien-3-one) 2 using anhydrous ZnCl₂ as catalyst. The spiroketalization was achieved efficiently via intramolecular cyclization of the Michael 1:2 adduct.     

Study of the Gas-Phase Intramolecular Aryltrifluoromethylation of Phenyl(Trifluoromethyl)Iodonium by ESI-MS/MS

The gas-phase reactions of the reactive λ ³-phenyl(trifluoromethyl)iodonium (PhI⁺(III)CF₃, 1 at m/z 273) to the radical cation of iodobenzene (PhI^?+, 2 at m/z 204) via the loss of ·CF₃ and the radical cation of trifluoromethylbenzene (PhCF₃ ^?+, 3 at m/z 146) via the loss of ·I, were studied by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Interestingly, the gas-phase intramolecular coupling reaction of CF₃ with phenyl via the CF₃ migration process of 1 at m/z 273 from iodine to the phenyl to give 3 at m/z 146 could only occur according to an intramolecular aromatic substitution mechanism. Density functional theory (DFT) calculations showed that the gas-phase intramolecular aryltrifluoromethylation of 1 at m/z 273 to 3 at m/z 146 occurred via a Meisenheimer complex intermediate (MC), where the triplevalent I center of 1 was reduced to monovalent I. Most importantly, the structure of 3 at m/z 146 derived from 1 at m/z 273 in ESI-MS/MS process was confirmed by comparison of its MS/MS with that of an authentic PhCF₃ ^?+ at m/z 146 acquired from the electron ionization (EI)-MS/MS analysis of PhCF₃. Thus, our studies revealed the intrinsic reactivity tendencies of λ³-phenyl(trifluoromethyl)iodonium under solvent-free conditions.      

Preparation, reactivity and tautomeric preferences of novel (1H-quinolin-2-ylidene)propan-2-ones

1,1-Difluoro-3-(1H-quinolin-2-ylidene)propan-2-one 1a, 1,1,1-trifluoro-3-(1H-quinolin-2-ylidene)propan-2-one 1b, 1,1,1-trifluoro-3-(4-chloro-1H-quinolin-2-ylidene)propan-2-one 1c and 1,3-dibromo-1,1-difluoro-3-(2-quinolyl)propan-2-one 2 are prepared and characterized by various spectroscopic techniques. The crystal structure of 1a is determined by X-ray diffraction. Furthermore, a series of previously known non-halogenated (1H-quinolin-2-ylidene)propan-2-ones 1d-1h are oxidized with AgBrO₃ in the presence of AlCl₃. In all cases, 2-(1-bromo-1-chloromethyl)quinoline 3 is obtained in high yield. The bromination order and sites of 1a are analyzed based on ab initio MP2 and DFT calculations for the molecule and its anions.     

Über die Synthese des 2,3,4,8-Tetrahydro [1] benzoxepino [5,4,3-ef]-1,4-benzodiazepin-3-ons

10-Nitro-6.11-dihydro-dibenz[b,e]oxepine-11-one (12) was obtained both from 2-nitro-6-phenoxymethyl-benzoic acid (8) by dehydration and from 2-nitro-6-phenoxymethyl-benzoyl chloride (10) by Friedel—Crafts-reaction.12 was reduced to the amino compound15 which yielded 10-aminoacetylamino-6.11-dihydro-dibenz[b, e]oxepine-11-one (19) on reaction with chloroacetyl chloride and subsequent treatment with ammonia. The cyclization of19 yielded the title compound (21). The behaviour of the ketons12 and15 against NH₂OH·HCl was investigated.     

Molecular and crystal structures of bis-tetrazolate ammonium salt and bis-tetrazole monohydrate

The title compounds bis-tetrazolate ammonium salt (I) and bis-tetrazole monohydrate (II) are synthesized and studied by single crystal and powder X-ray diffraction, IR and elemental analyses. Compound I crystallizes in the monoclinic space group C2/m, a = 8.8862(17) Å, b = 11.2334(21) Å, c = 3.7269(7) Å, β = 99.4(6)°, V = 367.03 ų (12), Z = 2. Compound II crystallizes in the monoclinic space group P2₁/c, a = 5.1701(9) Å, b = 4.7506(8) Å, c = 15.2197(24) Å, β = 107.2(7)°, V = 357.09(10) ų, Z = 2. In the structure of I, both ammonium cation and bis-tetrazolate counter-anion are located on twofold crystallographic axes, moreover, the bis-tetrazolate anion has a mirror plane passing through the ’C1-C1a bond. In the crystal structure of (II), the bis-tetrazole molecule sits on the twofold axis (bisecting the C1-C1a bond), whereas the solvent water molecule occupies a general position. In the crystal structure of (I), the molecules are packed via N-H…N intermolecular interactions. In the crystal structure of (II), the molecules are packed via N-H…O and O-H…O intermolecular interactions. In addition, the crystal packing of both structures is further strengthened by π-π stacking interactions.     

Electrochemical determination of acetaminophen in the presence of propranolol using an electrode modified with a Schiff base from 2-hydroxy-1-naphthaldehyde and ethylenediamine and multi-walled carbon nanotubes

A carbon paste electrode, modified with N,N′-bis-(2-hydroxy-1-naphthalidene)ethylenediamine and multi-walled carbon nanotubes (HNED-MWCNPE), was used for the determination of acetaminophen (ACOP) and propranolol (PP). Cyclic voltammetry (CV), chronocoulometry, chronoamperometry and differential pulse voltammetry (DPV) techniques were employed to study electro-oxidation of ACOP. The results revealed that the modified electrode showed an electrocatalytic activity toward the anodic oxidation of acetaminophen by a marked enhancement in the current response in buffered solution at pH 8.0. Some kinetic parameters such as the electron transfer coefficient (α) were also determined for the ACOP oxidation. The linear concentration range of 1 × 10^?3?1 × 10^?6 M with a detection limit of 4.6 × 10^?8 M (n = 16) for ACOP was obtained using DPV (pH 8.0). The modified electrode shows good sensitivity, selectivity and stability. The prepared electrode was also applied for the determination of ACOP in human blood serum.     

Structural characterization of a copper(II) complex containing oxidative cyclization of N-2-(4-picolyl)-N′-(4-methoxyphenyl)thiourea,new ligands of 4-picolylthiourea derivatives and the precursor molecular structure of oxidative cyclization of N-(2-pyridyl)-N′-(4-methoxyphenyl)thiourea

Three new compounds of aryl thiourea derivatives, namely N-2-(4-picolyl)-N′-(4-methoxyphenyl)thiourea (L1), N-2-(6-picolyl)-N′-(4-methoxyphenyl)thiourea (L2) and N-2-(4-picolyl)-N′-(4-nitrophenyl)thiourea (L3), and the new copper(II) complex [Cu(4PicTz4OMePh)(OAC)(EtOH)] (C1), as a result of oxidative cyclization of the ligand (L1), were synthesized. In addition, pure precursor (P1), as the product of the oxidative cyclization of N-(2-pyridyl)-N′-(4-methoxyphenyl)thiourea (L4), was isolated and characterized. Ligands (L1) and (L2) were characterized by ¹H and ¹³C NMR and single crystal X-ray analysis. ¹H NMR spectroscopy showed strong hydrogen bonding interactions between N′H-functionalities and the pyridine nitrogen atoms as well as weak intermolecular hydrogen bonding between the thione sulfur and the NH hydrogen. Structural studies of complex (C1) showed that the copper ion is five-coordinated with a square-pyramidal environment. The oxidative cyclization of ligand (L1) results in an anionic bidentate ligand in complex (C1). Both ligand (L1) and precursor (P1) crystallize as centrosymmetric dimers.     

The Ionization Mechanisms in Direct and Dopant-Assisted Atmospheric Pressure Photoionization and Atmospheric Pressure Laser Ionization

A novel, gas-tight API interface for gas chromatography–mass spectrometry was used to study the ionization mechanism in direct and dopant-assisted atmospheric pressure photoionization (APPI) and atmospheric pressure laser ionization (APLI). Eight analytes (ethylbenzene, bromobenzene, naphthalene, anthracene, benzaldehyde, pyridine, quinolone, and acridine) with varying ionization energies (IEs) and proton affinities (PAs), and four common APPI dopants (toluene, acetone, anisole, and chlorobenzene) were chosen. All the studied compounds were ionized by direct APPI, forming mainly molecular ions. Addition of dopants suppressed the signal of the analytes with IEs above the IE of the dopant. For compounds with suitable IEs or Pas, the dopants increased the ionization efficiency as the analytes could be ionized through dopant-mediated gas-phase reactions, such as charge exchange, proton transfer, and other rather unexpected reactions, such as formation of [M?+?77]⁺ in the presence of chlorobenzene. Experiments with deuterated toluene as the dopant verified that in case of proton transfer, the proton originated from the dopant instead of proton-bound solvent clusters, as in conventional open or non-tight APPI sources. In direct APLI using a 266 nm laser, a narrower range of compounds was ionized than in direct APPI, because of exceedingly high IEs or unfavorable two-photon absorption cross-sections. Introduction of dopants in the APLI system changed the ionization mechanism to similar dopant-mediated gas-phase reactions with the dopant as in APPI, which produced mainly ions of the same form as in APPI, and ionized a wider range of analytes than direct APLI. Graphical Abstract

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Syntheses and extraction properties of novel biscalixarene and thiacalix[4]arene hydrazone derivatives

By reacting thiacalix[4]arene with p-tosyloxyethoxylbenzaldehyde 1, 3-bis(benzaldehyde-4-oxyethyloxy)-p-tert-butylthiacalix[4]arene (2) were prepared in yield of 65%. Refluxing compound 2 with aniline, salicylic hydrazide, nicotinic hydrazide and isonicotinic hydrazide, novel ringopening 1,3-bis-arylformyl-hydrazone substituted thiacalix[4]arene derivatives (3a–3d) were obtained in yields of 77–89%. Refluxing compound 2 with o-phenylendiamine, oxalyl dihydrazide, malonic dihydrazide and adipic dihydrazide in “1 + 1” intermolecular condensation mode under diluted condition, novel 1,3-bis-acyl hydrazone-bridged calix[4]arene derivatives (4a–4d) were prepared in good yields. Moreover, by condensating compound 2 with 1,3-bis(hydrazinocarbonyl-methoxy)-p-tert-butylcalix[4]arene (5), the first example of hydrazone-bridged biscalixarene (6) with calix[4]arene and thiacalix[4]arene subunits was facilely synthesized in yield of 90%. The noncompetitive and competitive extracting experiments showed that these novel hosts were good receptors for both metal cations and α-amino acids. Compounds 3a–3d and 4a–4d showed similar binding properties with high extraction percentage but low extracting selectivities. Biscalixarene 6 exhibited not only high extracting abilities but also good extracting selectivities.     

Isomorphous crystal structures of 4,7,13,16,21,24-hexaoxo-1,10-diaziniabicyclo[8.8.8]·hexacosane bis(tribromide) and bis(bromoiodide)

Two compounds, 7,13,16,21,24-hexaoxa-1,10-diazoniabicyclo[8.8.8]hexacosane bis(tribromide) and bis(bromodiiodide) — [H₂(Crypt-222)]²⁺·2Br ₃ ^? (I) and [H₂(Crypt-222)]²⁺·1.45(BrI₂)^?·0.4(Br₂I)^?·0.15 I ₃ ^? (II) — are prepared and characterized by single crystal XRD; the refinement of the second compound was more accurate. Isomorphous monoclinic structures (I, space group C2/c, Z = 4, a = 12.090, b = 15.833 Å, c = 15.732 Å, β = 95.83°; II, a = 12.548 Å, b = 16.417 Å, c = 15.748 Å, β = 94.53°) are solved by a direct method and refined in the anisotropic full-matrix approximation to R = 0.057 (I) and 0.044 (II) using all 2635 (I) and 2852 (II) measured independent reflections (automated CAD-4 diffractometer, λMoK _α). In the structures of I and II one of the trihalide anions sits at the inversion center i(000), and the second trihalide anion and the dication [H₂(Crypt-222)]²⁺ are situated at crystallographic axis 2. In the structure of II iodine is located in the center of trihalide anions, while the terminal atoms are disordered and are represented by a statistical combination of iodine and bromine atoms.     

Gas Phase Decarbonylation and Cyclization Reactions of Protonated N-Methyl-N-Phenylmethacrylamide and Its Derivatives Via an Amide Claisen Rearrangement

Gas phase decarbonylation and cyclization reactions of protonated N-methyl-N-phenylmethacrylamide and its derivatives (M·H⁺) were studied by electrospray ionization-tandem mass spectrometry (ESI-MS/MS). MS/MS experiments of M·H⁺ showed product ions were formed by loss of CO, which could only occur with an amide Claisen rearrangement. Mechanisms for the gas phase decarbonylation and cyclization reactions were proposed based on the accurate m/z measurements and MS/MS experiments with deuterated compounds. Theoretical computations showed the gas phase Claisen rearrangement was a major driving force for initiating gas phase decarbonylation and cyclization reactions of M·H⁺. Finally, the influence of different phenyl substituents on the gas phase Claisen rearrangement was evaluated. Electron-donating groups at the para-position of the phenyl moiety promoted the gas phase Claisen rearrangement to give a high abundance of fragment ions [M ? CO + H]⁺. By contrast, electron-withdrawing groups on the phenyl moiety retarded the Claisen rearrangement, but gave a fragment ion at m/z 175 by loss of neutral radicals of substituents on the phenyl, and a fragment ion at m/z 160 by further loss of a methyl radical.     

New functionalization opportunities for <Emphasis Type="Italic">peri</Emphasis>-hydroxynaphthoyl and <Emphasis Type="Italic">peri</Emphasis>-fused heterocyclic compounds

A capability was studied of hydrogenated α-pyrone heterocycle in 7-methoxy-4-(4-methoxy-phenyl)-3,4-dihydro-2H-benzo[h]chromen-2-one to undergo aminolysis under the treatment with hydrazine hydrate, primary and secondary aliphatic and aromatic amines. A new approach was developed to the preparation of perihydroxyketone of naphthalene series containing a specific functional substituent in the ortho-position with respect to hydroxy group. The effect was revealed of an acetyl group in the position 9 of 7-methoxy-4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[h]chromen-2-one on the reaction of this compound with aliphatic amines and hydrazine hydrate. 9-Methoxy-1-(4-methoxyphenyl)-6-methyl-3H-benzo[de]pyrido[3,2,1-if]cinnolin-3-one [9-methyl-6-methoxy-3-(4-methoxyphenyl)-10,10a-diazapyren-1-one] was obtained, a new bis-peri-fused heteroaromatic system.     

Pharmacological evaluation of isochromen-1-ones and their thioanalogues derived from anti-inflammatory drug ketoprofen

The 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-one, 2 and their thio-analogues 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-thione, 3 and 3-{1-[3-(benzothioyl) phenyl]ethyl}-1H-isochromen-1-one, 5 were successfully obtained in good yield and purity from anti-inflammatory drug ketoprofen, 1 and its thio analogue, 4. The compounds were successfully characterized by FT-IR, MASS, ¹HNMR and ¹³CNMR spectral techniques. The in vitro anti-inflammatory and anti-oxidant screening revealed that 3-[1-(3-benzoylphenyl) ethyl]-1H-isochromen-1-one, 2 possesses better anti-oxidant and anti-inflammatory activity whereas 3-(1-(3-benzoylphenyl)ethyl)-1H-isochromene-1-thione, 3 and 3-(1-(3-benzothioyl) phenyl] ethyl}-1H-isochromen-1-one, 5 showed moderate anti-oxidant activity in comparison to ketoprofen.     

Enantioselective Supramolecular Carriers for Nucleoside Drugs. A Thermodynamic and Kinetic Gas Phase Investigation

The enantioselective interactions between chiral tetra-amidic receptors and nucleosides have been investigated by the ESI-IT-MS and ESI-FT-ICR-MS methodologies. Configurational effects on the CID fragmentation of diastereomeric [M ^H ₂ ?H?A]?⁺ aggregates (A?=?2'-deoxycytidine dC, citarabine (ara-C) were found to be mostly offset by isotope effect in [S ^X ₂ ?H?A]?⁺ (X?=?H, D) differently from the results obtained on the analogues (A?=?cytidine C and gemcitabine G). This result points the involvement of two different nucleoside/tetraamide isoforms. The structural differences of the [M ^H ₂ ?H?A]?⁺ (A?=?C and G) complexes vs. the [M ^H ₂ ?H?A]?⁺ (dC and ara-C) ones is fully confirmed by the kinetics of their uptake of the 2-aminobutane enantiomers, measured by FT-ICR mass spectrometry. Indeed, uptake of the 2-aminobutane enantiomers by [M ^H _n ?H?A]?⁺ (n?=?1,2; A?=?dC and ara-C) complexes is reversible, while that by [M ^H _n ?H?A]?⁺ (n?=?1,2; A?=?C and G) is not. The most encouraging result concerning the measured fragmentation and kinetic differences between C and ara-C, that are just epimers, indicates the possibility to subtly modulate the non-covalent drug/receptor interactions, through the electronic properties of the 2'-substituent on the nucleoside furanose ring, and furthermore on its three-dimensional position.     

First total synthesis and stereochemical revision of okaramine M

We describe the first total synthesis of the reported and revised structures of okaramine M (1 and 7) through the Ugi three-component reaction of pyrroloindole imine 10 with p-methoxyphenyl isonitrile and N-Boc-l-tryptophan, followed by cyclization and epimerization.     

Anion-directed organized assemblies of protonated pyrazole-based ionic salts

The reactions of 3(5)-(4-methoxyphenyl)-5(3)-phenyl-1H-pyrazole (L ¹ ) with nitric acid and 5-(4-benzyloxyphenyl)-3-(furan-2-yl)-1H-pyrazole(L ² ) with hydrochloric acid produced [HL ¹ · NO₃] (Salt-1) and [HL ² · Cl] (Salt-2). The structures of Salt-1 and Salt-2 were determined by single crystal X-diffraction. In Salt-1, HL ¹ showed [2 + 2] binding of NO₃ ^? ions in the solid state to form dimer architecture with R ₁ ² (4) and R ₄ ⁴ (14) graph sets. An anion directed one-dimensional anion-assisted helical chain with active participation of the chloride ion and protonated pyrazole via N–H···Cl hydrogen bonding in Salt-2. In addition, the protonated HL ² molecules interacted with each other through weak C–H···π interactions resulting in the formation of another one-dimensional helical chain.