A novel membrane sensor for histamine H1-receptor antagonist "fexofenadine".

The construction and general performance of thirteen new polymeric membrane sensors for the determination of fexofenadine hydrochloride based on its ion exchange with reineckate, tetraphenylborate and tetraiodomercurate have been studied. The effects of membrane composition, type of plasticizer, pH value of sample solution and concentration of the analyte in the sensor internal solution have been thoroughly investigated. The novel sensor based on reineckate exchanger shows a stable, potentiometric response for fexofenadine in the concentration range of 1 x 10(-2) - 2.5 x 10(-6) M at 25 degrees C that is independent of pH in the range of 2.0 - 4.5. The sensor possesses a Nernstian cationic slope of 62.3+/-0.7 mV/concentration decade and a lower detection limit of 1.3 x 10(-6) M with a fast response time of 20 - 40 s. Selectivity coefficients for a number of interfering ions and excipients relative to fexofenadine were investigated. There is negligible interference from almost all studied cations, anions, and pharmaceutical excipients, however, citrizine that has a structure homologous to that of fexofenadine was found to interfere. The determination of fexofenadine in aqueous solution shows an average recovery of 99.83% with a mean relative standard deviation (RSD) of 0.5%. Direct potentiometric determination of fexofenadine in tablets gave results that compare favorably with those obtained by standard spectrophotometric methods. Potentiometric titration of fexofenadine with phosphomolybdic acid as a titrant has been monitored with the proposed sensor as an end point indicator electrode.     

Spectrophotometric determination of H(2)-receptor antagonists via their oxidation with cerium(IV)

A simple, accurate and sensitive spectrophotometric method has been developed and validated for determination of H(2)-receptor antagonists: cimetidine, famotidine, nizatidine and ranitidine hydrochloride. The method was based on the oxidation of these drugs with cerium(IV) in presence of perchloric acid and subsequent measurement of the excess Ce(IV) by its reaction with p-dimethylaminobenzaldehyde to give a red colored product (lambda(max) at 464nm). The decrease in the absorption intensity of the colored product (DeltaA), due to the presence of the drug was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9990-0.9994) were found between DeltaA values and the concentrations of the drugs in a concentration range of 1-20microgml(-1). The assay limits of detection and quantitation were 0.18-0.60 and 0.54-1.53microgml(-1), respectively. The method was validated, in terms of accuracy, precision, ruggedness and robustness; the results were satisfactory. The proposed method was successfully applied to the determination of the investigated drugs in pure and pharmaceutical dosage forms (recovery was 98.3-102.6+/-0.57-1.90%) without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods.     

Molecular modelling studies on the ORL1-receptor and ORL1-agonists

The ORLI (opioid receptor like 1)- receptor is a member of the family of rhodopsin-like G protein-coupled receptors (GPCR) and represents an interesting new therapeutical target since it is involved in a variety of biomedical important processes, such as anxiety, nociception, feeding, and memory. In order to shed light on the molecular basis of the interactions of the GPCR with its ligands, the receptor protein and a dataset of specific agonists were examined using molecular modelling methods. For that purpose, the conformational space of a very potent non-peptide ORL1-receptor agonist (Ro 64-6198) with a small number of rotatable bonds was analysed in order to derive a pharmacophoric arrangement. The conformational analyses yielded a conformation that served as template for the superposition of a set of related analogues. Structural superposition was achieved by employing the program FlexS. Using the experimental binding data and the superposition of the ligands, a 3D-QSAR analysis applying the GRID/GOLPE method was carried out. After the ligand-based modelling approach, a 3D model of the ORL1-receptor has been constructed using homology modelling methods based on the crystal structure of bovine rhodopsin. A representative structure of the model taken from molecular dynamics simulations was used for a manual docking procedure. Asp-130 and Thr-305 within the ORL1-receptor model served as important hydrophilic interaction partners. Furthermore, a hydrophobic cavity was identified stabilizing the agonists within their binding site. The manual docking results were supported using FlexX, which identified the same protein-ligand interaction points.     

1H NMR studies of nickel(II) complexes of n-hydroxylpropyl-salicylaldimines

The¹H NMR spectra of various monomeric, dimeric and trimeric complexes of Ni(II) with n-hydroxypropyl-salicylaldimines have been measured and assigned. They are consistent with structures previously proposed for these complexes.     

Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation

Summary A modelling study has been carried out, investigating the binding of histamine (Hist), 2-methylhistamine (2-MeHist) and 2-phenylhistamine (2-PhHist) at two postulated agonistic binding sites on transmembrane domain 5 (TM5) of the histamine H₁-receptor. For this purpose a conformational analysis study was performed on three particular residues of TM5, i.e., Lys²⁰⁰, Thr²⁰³ and Asn²⁰⁷, for which a functional role in binding has been proposed. The most favourable results were obtained for the interaction between Hist and the Lys²⁰⁰/Asn²⁰⁷ pair. Therefore, Lys²⁰⁰ was subsequently mutated and converted to an alanine, resulting in a 50-fold decrease of H₁-receptor stimulation by histamine. Altogether, the data suggest that the Lys²⁰⁰/Asn²⁰⁷ pair is important for activation of the H₁-receptor by histamine. In contrast, analogues of 2-PhHist seem to belong to a distinct subclass of histamine agonists and an alternative mode of binding is proposed in which the 2-phenyl ring binds to the same receptor location as one of the aromatic rings of classical histamine H₁-antagonists. Subsequently, the binding modes of the agonists Hist, 2-MeHist and 2-PhHist and the H₁-antagonist cyproheptadine were evaluated in three different seven--helical models of the H₁-receptor built in homology with bacteriorhodopsin, but using three different alignments. Our findings suggest that the position of the carboxylate group of Asp¹¹⁶ (TM3) within the receptor pocket depends on whether an agonist or an antagonist binds to the protein; a conformational change of this aspartate residue upon agonist binding is expected to play an essential role in receptor stimulation.Abbreviations 2-MeHist 2-methylhistamine - 2-PEA 2-pyridyl-ethylamine - 2-PhHist 2-phenylhistamine - CHO Chinese hamster ovary - E_int interaction energy - E_str strain energy - GES global energy structure - gpH₁R guinea pig H₁-receptor - GPCR G-protein coupled receptor - Hist histamine - N proximal nitrogen - N tele nitrogen - TM transmembrane domain - WT wild type     

1H and 13C NMR studies of (phenylethynyl) (triphenylphosphine) gold(I)

A ¹H and ¹³C NMR study of (phenylethynyl) (triphenylphosphine) gold(I) is presented. Contrary to the solid state findings, the existence of Au … Au contacts in solution can be excluded on the basis of experimental results. The ¹³C chemical shifts of various Au, Ag and Cu triphenylphosphine complexes and the corresponding SCS values are considered to rationalize the electronic behaviour of the ligand on complexation.     

A novel synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

A new synthesis of N₁-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R₁ substituents.     

Spectroscopic studies on methyl torsional behavior in 1-methyl-2(1H)-pyridone, 1-methyl-2(1H)-pyridinimine, and 3-methyl-2(1H)-pyridone. I. Excited state

The laser induced fluorescence excitation and dispersed fluorescence spectra of three nitrogen heterocyclic molecules 1-methyl-2(1H)pyridone (1MPY), 1-methyl-2(1H)pyridinimine (1MPI), and 3-methyl-2(1H)pyridone (3MPY) have been studied under supersonic jet cooled condition. The methyl torsional and some low frequency vibrational transitions in the fluorescence excitation spectrum were assigned for 1MPY. These new assignments modify the potential parameters to the methyl torsion reported earlier. Some striking similarities exist between the torsional and vibrational transitions in the fluorescence excitation spectra of 1MPY and 1MPI. Apart from pure torsional transitions, a progression of vibration-torsion combination bands was observed for both these molecules. The excitation spectrum of 3MPY resembles the spectrum of its parent molecule, 2-pyridone. The barrier height of the methyl torsion in the excited state of 3MPY is highest amongst all these molecules, whereas the barrier in 1MPI is higher than that of 1MPY. To get an insight into the methyl torsional barrier for these molecules, results of the ab initio calculations were compared with the experimental results. It was found that the conformation of the methyl group undergoes a 60 degrees rotation in the excited state in all these molecules with respect to their ground state conformation. This phase shift of the excited state potential is attributed to the pi*-sigma* hyperconjugation between the out-of-plane hydrogen of the methyl group and the molecular frame. It has been inferred that the change in lowest unoccupied molecular orbital energy plays the dominant role in the excited state barrier formation.     

A novel class of tetrairon(III) single-molecule magnets with graphene-binding groups

Tripods of general formula R’–O–CH₂C(CH₂OH)₃ are excellent site-specific ligands for the preparation of functionalized Fe₄ single-molecule magnets. Herein, we describe the synthesis and characterization of two novel complexes designed to bind graphene surfaces, in which the R group consists of an alkyl spacer –(CH₂)_n– (n = 6 and 10) and a terminal pyrenyl moiety. The site-specific ligand substitution on [Fe₄(OMe)₆(dpm)₆] (Hdpm = dipivaloylmethane) with the new tripods has been studied with ²H NMR on isotopically-enriched samples, revealing that, once formed, these clusters are stable in solution over long timescales. It was not possible to isolate the new compounds as crystalline solids, nevertheless they were chemically characterized by elemental analysis and ¹H NMR. The presence of the pyrenyl ending groups prompted us to investigate the effect of metal complexation on fluorescence, and a full pyrene-to-iron cluster excitation energy transfer was observed. The analysis of the magnetic behaviour revealed an S = 5 ground spin state with a negative zero-field splitting parameter D = ?0.42 cm^?1.     

A facile and novel synthesis of 1,6-naphthyridin-2(1H)-ones

A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described. In the first scheme 5-acetyl-6-[2-(dimethylamino)ethenyl]-1,2-dihydro-2-oxo-3-pyridinecarbonitrile ( 4 ) obtained by the reaction of N,N-dimethylformamide dimethyl acetal with 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile ( 3 ) was cyclized to 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile ( 5 ) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5-methyl-1,6-naphthyridin-2(1H)-one ( 8 ) and its dimer 9 . Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one ( 12 ) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one ( 13 ). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5-acyl(aroyl)-6-methyl-2(1H)-pyridinones ( 21 ) which in turn were treated with Bredereck's reagent to produce 5-acyl(aroyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinones ( 22 ). Treatment of 22 with ammonium acetate led to the formation of 1,6-naphthyridin-2(1H)-ones 23 .     

Efficient synthesis of novel quinazoline-4(1H)-one derivatives by N-halosulfonamides

Research on Chemical Intermediates - In this research, a facile, effective and one-pot synthesis of new quinazoline-4(1H)-one derivatives is reported. Isatoic anhydride, acid hydrazides or ammonium...     

Synthesis of novel 3-(1,3-thiazol-2-yl)-7,8-dihydroquinoline-2,5(1H,6H)-diones

An efficient method for the synthesis of novel 3-(1,3-thiazol-2-yl)-7,8-dihydroquinoline-2,5(1H,6H)-diones from various 2-dimethylaminomethylidenecyclohexane-1,3-diones, (1,3-thiazol-2-yl)acetonitriles, and dimethylformamide dimethyl acetal was developed. These transformations proceeded through intermediate 2-[2-(4-aryl-1,3-thiazol-2-yl)-2-cyanoethenyl]-3-oxocyclohex-1-en-1-olates. They were isolated as piperidinium salts and used in further heterocyclization reactions with aromatic amines, giving novel 1-aryl-3-(1,3-thiazol-2-yl)-7,8-dihydroquinoline-2,5(1H,6H)-diones. These compounds were also obtained by preparative three-step “one pot” synthesis under controlled microwave irradiation. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 412–417, February, 2008.     

NMR studies of 4(3H)-quinazolinones and 4(3H)-quinazolinethiones

Summary Unambiguous¹H and¹³C NMR assignments for 4(3H)-quinazolinones1–6 and their corresponding 4-thiones7–12 have been made. This resulted in the revision of the previous assignments for the two benzenoid carbons (C-5 and C-8) of quinazolinones1,2,4, and5. Thionation of the nucleophilic amides1–6 has been found to cause a distinct change in the¹³C chemical shift of particularly C-4, but also of those of C-4a, C-5, and C-8a. One-bond and several long range heteronuclear coupling constants for the compounds have also been measured.

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Kernresonanzspektroskopie von 4(3H)-Chinazolinonen und 4(3H)-Chinazolinthionen

Zusammenfassung Die¹H- und¹³C-NMR-Spektren der 4(3H)-Chinazolinone1–6 und ihrer entsprechenden 4-Thione7–12 wurden zugeordnet. Dabei zeigte sich, daß eine frühere Zuordnung der beiden benzoiden Kohlenstoffe (C-5 und C-8) der Chinazolinone1,2,4 und5 falsch war. Ersatz des Sauerstoffs durch Schwefel in den nukleophilen Amiden1–6 führt insbesondere für C-4, aber auch für C-4a, C-5 und C-8a zu einer deutlichen Änderung der chemischen Verschiebung. Heteronukleare Kopplungskonstanten über eine und über mehrere Bindungen wurden bestimmt.

     

On the mechanism of a novel 3(2H)-Furanone-2(5H)-furanone rearrangement

The isolation of a stable intermediate product and the mechanism of a novel 3(2H)-furanone-2(5H)-furanone rearrangement that led to the facile preparation of a new class of γ-lactone amides 2 and 4 are discussed.     

DFT studies of the conformational/structural dependencies of geminal 1H,1H scalar coupling 2J(H,H') in substituted methanes

A study is presented of the structural dependencies for scalar, interproton J-coupling across two bonds in a series of substituted methanes. The coupled perturbed, density functional theory method with a B3PW91 functional and aug-cc-pVTZ-J basis sets is used to examine coupling between geminal protons (2)J(H,H') in methane and a series of substituted compounds CH(3)X (X = CH3, CH(2)CH(3), CH=CH2, CH=O, and NH2) as functions of the dihedral angle phi measured about the C1-X2 bonds. All four contributions are obtained but all conformational effects are dominated by the Fermi contact term. Simple linear combination of atomic orbitals (LCAO)-molecular orbital (MO) sum-over-states methods are used to examine the relationships of the coupling constants with dihedral angles as well as internal H-C-H and H-C1-X2 angles. This study explores some novel aspects of geminal H-H coupling including an analysis of the asymmetry in the conformational dependencies arising from non-next-nearest neighbor interactions. For each of the substituted methanes, explicit trigonometric/exponential expressions are given and these accurately reproduce the (2)J(H,H') structural dependencies with standard deviations usually less than 0.03 Hz. The molecular structures for representative bicyclic molecules were fully optimized, and DFT results for (2)J(H,H') reproduce all the trends in the experimental data. A discussion is given on the applicability of the equations for H--H coupling in the substituted methanes to coupling in the bicyclic molecules.     

Five-coordinate iron(III) porphycenes: (1)H NMR, magnetic, and structural studies

Five-coordinate iron(III) 2,7,12,17-tetrapropylporphycene (TPrPc)Fe(III)X (X = C(6)H(5)O(-), Cl(-), Br(-), I(-), ClO(4)(-)) complexes have been investigated. The (1)H NMR spectra demonstrate downfield shifts for pyrrole resonances [(TPrPc)Fe(III)(C(6)H(5)O), 65.3 ppm; (TPrPc)Fe(III)Cl, 28.5 ppm] but large upfield ones for (TPrPc)Fe(III)Br (-7.8 ppm), (TPrPc)Fe(III)I (-49.4 ppm), and (TPrPc)Fe(III)ClO(4) (-77.1 ppm) (294 K, CD(2)Cl(2)). The pyrrole chemical shifts span the remarkable +70 to -80 ppm range. The variable-temperature (1)H NMR spectra of (TPrPc)Fe(III)X demonstrate anti-Curie behavior with a sign reversal for (TPrPc)Fe(III)Cl. These behaviors are consistent with the admixed S = 3/2, 5/2 ground electronic state with a dominating contribution of the S = 3/2 one. In terms of the chemical shift, (TPrPc)Fe(III)(ClO(4)) can be considered as an example of the purest S = 3/2 state in the investigated series. The extent of the S = 5/2 contribution in the admixed S = 3/2, 5/2 ground electronic state, as gradated solely the basis of the pyrrole proton paramagnetic shifts, is controlled by the strength of the axial ligand, following the magnetochemical series (Evans, D. R.; Reed, C. A. J. Am. Chem. Soc. 2000, 122, 4660). Significantly iron(III) 2,7,12,17-tetrapropylporphycene, soluble in typical organic solvents, can be considered as a universal framework to classify the ligand strength in a magnetochemical series, consistently using the beta-H pyrrole paramagnetic shifts as a fundamental criterion. The structure of (TPrPc)Fe(III)Cl has been determined by X-ray crystallography. The iron is five-coordinate with bonds of nearly equal length to the four pyrrole nitrogen atoms (Fe-N in the range 1.983(5)-2.006(6) A). The iron lies 0.583(1) A out of the mean plane of the macrocycle and 0.502(5) A out of the mean N(4) plane. In the solid, pairs of molecules are positioned about the center of symmetry so there is face-to-face pi-pi contact. The mean plane separation is 3.38 A, and the lateral shift of the porphycene center along the Fe-N bond is 4.490 A. The distance from one porphycene center to the other is 5.62 A, and the iron-iron separation is 6.304(2) A.     

A novel class of antiulcer agents. 4-Phenyl-2-(1-piperazinyl)quinolines

The synthesis of a novel class of antiulcer agents, the substituted 4-phenyl-2-(1-piperazinyl)quinolines, and their pharmacological activities (inhibitory effects on hypothermia induced by reserpine and on gastric ulcers induced by stress or ethanol) are described. These compounds can be classified into three groups (a group predominantly effective on the stress-induced ulcer, one effective on both the stress- and ethanol-induced ulcers, and one selectively effective on the ethanol-induced ulcer), with regard to antiulcer activity. The inhibitory effect on stress-induced ulcer was found to be in close relation to the antagonism of hypothermia. The structure-activity relationships in these compounds are described. Among the compounds, 2-(4-ethyl-1-piperazinyl)-4-phenylquinoline dimaleate (9, AS-2646) showed a potent inhibition of stress-induced ulcer and gastric acid secretion, possively through action on the central nervous system, and it was selected for clinical evaluation.