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PubMed1986

Pharmacokinetic profile of imidazole 2-hydroxybenzoate, a novel nonsteroidal antiinflammatory agent.

Imidazole 2-hydroxybenzoate is a novel nonsteroidal antiinflammatory agent which clinico-pharmacologically and pharmacokinetically has to be understood as imidazole and salicylic acid. The pharmacokinetic profile of both components after single and multiple oral (tablets, drops), and topical administration (gel 5%)--the latter in a pilot study--was evaluated as well as protein-binding, relative bioavailability and the metabolic pattern. Absorption and elimination of the two compounds were fast. All essential pharmacokinetic and bioavailability parameters seem to be in a good agreement with data published in the literature and an accumulation tendency was not observed. The t1/2 beta for imidazole (oral administration) was determined for a single dose at 2.98 +/- 1.13 h, for a multiple dose (last dose) at 1.86 +/- 0.78 h; for salicylic acid the t1/2 beta for a single dose was determined at 6.46 +/- 3.79 h and for a multiple dose (last dose) at 6.40 +/- 3.36 h. The protein-binding of imidazole was in the range of 5-15% and of salicylic acid of about 80-85%. The relative bioavailability was calculated for imidazole (single dose) at 138% and for multiple dosing (last dose) at 113%; for salicylic acid the values for single dose were 148% and for multiple dosing (last dose) 128%. The tolerability was altogether good and no adverse reactions could be observed. The topical administration (pilot study) with gel 5% did not show any systemic effects or adverse reactions. The local tolerability was very good. Statistically, there were only slight differences between tablets and drops overall since only one p-value was less than 0.01. According to the small sum of squared residuals, the NONLIN-program performed an excellent fitting of the data to the model equation.

Administration, Cutaneous↗
PubMed1980

A study of the mechanism of ferritin formation. The effect of pH, ionic strength and temperature, inhibition by imidazole and kinetic analysis.

The rate of ferritin formation in the buffers 4-morpholinepropanesulphonic acid (Mops), 4-morpholineethanesulphonic acid (Mes) and imidazole at pH values from 5.0 to 6.5 is quite similar. However, the rate of iron deposition is much greater in Mops and Mes at pH values above 6.5 than in imidazole. Increasing the concentration of imidazole inhibits ferritin formation and also leads to a transformation in the shape of the kinetic curves observed. This inhibiton is also observed at constant ionic strength but is not found for non-complexing buffers such as Mops. An inhibition of ferritin formation in imidazole and in Mops buffers is also observed with increasing ionic strength. We conclude that the unprotonated form of imidazole inhibits iron deposition, possibly by binding to the active site of the apoferritin molecule. The temperature dependence of iron deposition was examined. An optimum temperature of 50 degrees C was found but the Arrhenius plots were non-linear. On the basis of these and previous results, a kinetic model is developed which accounts well for ferritin formation at pH values below 6.5 and above 7.0 in non-complexing buffers. The model does not account for the kinetics observed at pH values close to neutrality.

Alkanesulfonates↗
PubMed1984

Purification of liver microsomal cytochrome P-450 isozymes 3a and 6 from imidazole-treated rabbits. Evidence for the identity of isozyme 3a with the form obtained by ethanol treatment.

Two forms of cytochrome P-450 have been purified to electrophoretic homogeneity from hepatic microsomes of rabbits treated with imidazole. Several criteria indicate that the cytochrome of higher electrophoretic mobility is identical with ethanol-inducible isozyme 3a. "Imidazole-3a" and "ethanol-3a" exhibit the same chromatographic characteristics and have identical electrophoretic mobilities upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Furthermore, the two protein preparations have the same absorbance maxima and absorption coefficients in the oxidized, reduced, and reduced-CO states. A single immunoprecipitin band exhibiting complete identity was observed upon reaction of imidazole-3a and ethanol-3a with the immunoglobulin G fraction from sheep immunized with the latter protein. The amino acid composition and first 10 residues of the amino terminus of the two protein preparations are indistinguishable, as are the high-performance liquid chromatographic maps of the peptides obtained upon cleavage with trypsin, Staphylococcus aureus V8 protease, or Lys C endoproteinase . Furthermore, these preparations have very similar activities in the oxidation of ethanol to acetaldehyde and the p-hydroxylation of aniline. Evidence was obtained that the cytochrome of lower electrophoretic mobility isolated from imidazole-treated rabbits is probably identical with isozyme 6; the spectral characteristics, amino acid composition, and carboxyl-terminal sequence are described. As an inducer, imidazole has the advantage over ethanol of being less variable in its effects and requiring a shorter period of treatment. From the resulting liver microsomes, one can readily isolate, in addition to P-450 isozymes 3a and 6, isozymes 3c and 4 as well as epoxide hydrolase.

Amino Acids↗
PubMed1980

Imidazole derivatives with potential biological activity.

A series of 1-substituted imidazole-5-carbohydroxamic acids Ia, Ib and Ic were prepared from the corresponding 5-methoxycarbonyl imidazoles (IX) obtained by a univocal synthesis starting with the reaction of the amines (III) with ethylchloroacetate. On treatment of 4(5)-methoxycarbonyl imidazoles (XI) with alkylaryl halides (X), on the contrary, mixtures of 1-substituted-4(or 5)-methoxycarbonyl imidazoles were obtained that, when separated by thin-layer chromatography, gave the carbohydroxamic acids Ia, Ib, Id and Ie and IIa leads to f. The structure of the imidazole derivatives were obtained by means of IR, NMR and UV spectra. On carrying out tests of biological activity on these compounds, it had been found that the 5-carbohydroxamic acids possess, compared to the 4-carbohydroxamic ones, a greater activity. Particularly Ib and Ib--HCl seem fairly active against Klebsiella pneumoniae and Clostridium bifermentans, Ib--HCl against Bacillus subtilis, too.

Anti-Bacterial Agents↗
PubMed1980

Effect of imidazole on oxytocin and acetylcholine induced responses in isolated rat uterus: with observations on its mechanism of action.

Imidazole (3.67 x 10(-3) M) and sodium bicarbonate (1.78 x 10(-2) M) failed to alter acetylcholine evoked responses in isolated rat uterus but they produced a significant shift of the log dose-response curve of oxytocin to the left. This potentiating effect was reversible. Addition of imidazole increased the pH of de Jalon solution from 7.2 to 8.5. Sodium dihydrogen orthophosphate (3.3 x 10(-3) M) prevented the change of pH due to the addition of imidazole and at the same time the potentiating effect of imidazole was inhibited. The present study strongly suggests that the potentiation of oxytocin-evoked responses by imidazole is due to the change in pH of de Jalon solution towards more alkaline range and it may not be due to stimulation of phosphodiesterase activity of rat uterus.

Acetylcholine↗
PubMed1993

Calmodulin-dependent nitric-oxide synthase. Mechanism of inhibition by imidazole and phenylimidazoles.

Calmodulin-dependent nitric-oxide synthase from bovine brain and GH3 pituitary cells is inhibited by imidazole, 1-phenylimidazole, 2-phenylimidazole, and 4-phenylimidazole, with half-maximal inhibition occurring at 200, 25, 160, and 600 microM concentrations of inhibitor, respectively. Imidazole inhibits the maximal velocity of citrulline formation by the enzyme, but does not alter the concentration of arginine, calmodulin, or (6R)-5,6,7,8,-tetrahydro-L-biopterin required for expression of half-maximal activity. Imidazole, 1-phenylimidazole, 2-phenylimidazole, and 4-phenylimidazole had no effect on calmodulin-dependent reduction of cytochrome c by the enzyme at concentrations up to 50-fold higher than those that inhibited citrulline formation. Imidazole inhibited calmodulin-dependent NADPH consumption by the enzyme with dissolved oxygen as the sole electron acceptor, with half-maximal inhibition occurring at a concentration of 225 microM. These observations are consistent with the proposal that imidazole and phenylimidazoles inhibit citrulline formation and oxygen reduction by acting as a sixth coordination ligand of the heme iron. This interaction prevents the formation of the activated reduced species of oxygen necessary for the formation of citrulline.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

[The effect of dimethyl-(imidazol-1-yl) methanesulfonic acid on experimental atherogenesis in rabbits].

The hypocholesterolemic and antiatherosclerotic activities of the new imidazole derivative dimethyl-(imidazole-1-yl) methanesulfonic acid (1273) were investigated in rabbits fed through a probe either cholesterol, 200 mg/kg body weight, suspended in sunflower seed oil or that supplemented by imidazole, 15 mg/kg body weight, or its derivative 1273, 30 mg/kg body weight. Total cholesterol showed an 8-fold increase in all rabbit groups as compared to that in the animals fed a routine laboratory chow. In the agent 1273-given animals, the aortic atherosclerotic lesion index (ALI) was 7.8%, which was 2.4 times lower that in hypercholesterolemic animals untreated with this agent or treated with imidazole. Concurrently with a decrease in the aortic ALI, the agent 1273 lowered the rabbit hepatic levels of free and esterified cholesterol. The experimental findings of cultured rabbit hepatocytes suggest that the agent 1273 reduces hepatic cholesterol levels by inhibiting the de novo cholesterol synthesis. In vitro studies on murine J774 macrophages have demonstrated that inhibition of cholesterol esterification in the vascular wall macrophages is one of the possible mechanisms responsible for the antiatherosclerotic activity of this derivative of imidazole.

Animals↗
PubMed1994

Changes of organ blood flow and cardiac output after imidazole administration.

Effects of imidazole, an inhibitor of thromboxane synthesis (10 mg/kg bw., iv.) on the distribution of cardiac output and intrarenal hemodynamics were investigated in normovolemic (free water and salt uptake before the experiment) narcotized rats. The cardiac output was measured on the basis of the Stewart-Hamilton principle, the blood flow of the organs by the Sapirstein method. 86Rb was used as indicator. One hour following the imidazole administration while mean arterial blood pressure remained constant a slight drop in the cardiac output (CO) was observed (CO-control: 24.1 +/- 4.77; CO-imidazole: 20.6 +/- 2.40 ml/min/100 g; p < 0.05) and total peripheral resistance increased (TPR-control: 42.3 +/- 9.27; TPR-imidazole: 48.3 +/- 7.05 R; p < 0.05). The vascular resistance in the heart, lungs (bronchial fraction), liver, spleen, intestine and adrenal glands remained unchanged. The blood flow of the skin and skeletal muscle decreased moderately, their vascular resistance increased following imidazole treatment. Inhibition of the thromboxane synthesis did not influence the renal and intrarenal (cortex and medulla) circulation, the percentile distribution of the intrarenal blood flow remained unchanged. The results suggest that TXA2 does not play a definite role in maintaining the a) vascular tone (blood flow) of different organs b) intrarenal hemodynamics (salt and water excretion) in normovolemic rats.

Animals↗
PubMed1998

Carnosine and other imidazole-containing compounds enhance the postdenervation depolarization of the rat diaphragm fibres.

In the presence of carnosine, anserine, histidine, imidazole and 7-nitro indazole, the early postdenervation depolarization of muscle of about 8 mV was significantly increased by 2.15-4.8 mV. The presence of the imidazole ring in the molecule is apparently necessary for this effect. These compounds also eliminated an NO-mediated protective effect of L-glutamate and carbachol on the depolarization of membrane potential. The presence of imidazole, 7-nitro indazole, carnosine and anserine did not significantly change the effect of an external NO donor, sodium nitroprusside. The structural and functional similarity between imidazole derivatives and the known NO synthase inhibitor, 7-nitro indazole suggests that imidazole, carnosine and anserine might act by inhibiting NO production which is stimulated by glutamate and carbachol.

Animals↗
PubMed2003

The silica-like extended polymorphism of cobalt(II) imidazolate three-dimensional frameworks: X-ray single-crystal structures and magnetic properties.

Five polymorphous frameworks of cobalt(II) imidazolates (1-5) have been prepared by solvatothermal syntheses. Of these, compound 3 has already been synthesized in a gas-phase reaction by Seel et al. in 1969 and structurally characterized by Sturm et al. in 1975. The new synthetic strategy affords four polymorphous frameworks of cobalt(II) imidazolates (1, 2, 4, 5) of crystalline substances, of which the compound 4 (a = b = 23.450(3), c = 12.460(3) A, tetragonal, I4(1)cd, Z = 16) is an isomorphous compound of [Zn(im)(2)]( infinity ), which was also synthesized in a gas-phase reaction in 1980. The frameworks of compounds 1 and 2 are porous and isostructural; they have the same framework topology that represents a novel uninodal (6,4)-net: 1: a = 18.513(4), b = 24.368(5), c = 9.2940(19) A, orthorhombic, Fdd2, Z = 16; 2: a = 17.635(4), b = 27.706(6), c = 9.0810(18) A, orthorhombic, Fdd2, Z = 16. The framework of compound 5 exhibits a topology of zeolitic structure with the unit-cell parameters: a = 24.3406(8), b = 9.4526(3), c = 24.8470(8) A, beta = 91.977(1) degrees, monoclinic, P2(1)/n, Z = 4. All polymorphous frameworks of cobalt(II) imidazolates reflect the structural features of silica (SiO(2)) and also exhibit different magnetic behaviors, although the imidazolates transmit the antiferromagnetic coupling between the cobalt(II) ions in all cases. However, the uncompensated antiferromagnetic couplings arise from spin-canting are sensitive to the structures: compound 1 is an antiferromagnet with T(N) = 13.11 K; compounds 2-4 are weak ferromagnets (canted antiferromagnets): 2 shows a very weak ferromagnetism below 15 K, 3 exhibits a relatively strong ferromagnetism below 11.5 K and a coercive field (H(C)) of 1800 Oe at 1.8 K, and 4 displays the strongest ferromagnetism of the three cobalt imidazolates and demonstrates a T(C) of 15.5 K with a coercive field, H(C), of 7300 Oe at 1.8 K. However, compound 5 seems to be a hidden canted antiferromagnet with a magnetic ordering temperature of 10.6 K.

Journal Article↗
PubMed1991

Rilmenidine lowers arterial pressure via imidazole receptors in brainstem C1 area.

We sought to determine the site of action and receptor type responsible for the antihypertensive actions of rilmenidine, an oxazoline analogue of clonidine. In anesthetized paralyzed rats decerebration did not alter the dose dependent reductions in arterial pressure and heart rate elicited by i.v. drug. Rilmenidine microinjected bilaterally into the C1 area of the rostral ventrolateral medulla (RVL), but not nucleus tractus solitarii (NTS) nor caudal ventrolateral medulla (CVL), elicited dose-dependent falls in arterial pressure and heart rate at doses an order of magnitude less than required systemically. Prior microinjection into the C1 area of the selective alpha 2-adrenoceptor antagonist SKF-86466, even at high doses, failed to modify the hypotension to i.v. rilmenidine. However, microinjection of 3- to 10-fold lower doses of idazoxan, a ligand for imidazole as well as alpha 2-adrenoceptors, blocked the effects. Rilmenidine also competed with the clonidine analogue [3H]p-aminoclonidine ([3H]PAC) at specific binding sites in membranes of bovine ventrolateral medulla and frontal cortex. In RVL rilmenidine competed with binding to imidazole and alpha 2-adrenergic binding sites with a 30-fold selectivity for the imidazole binding sites. In frontal cortex binding was of lower affinity and restricted to alpha 2-adrenergic sites. We conclude that rilmenidine, like clonidine, acts to lower arterial pressure by an action on imidazole receptors in the C1 area of RVL. The higher selectivity of rilmenidine for imidazole to alpha 2-adrenoceptors as compared to clonidine may explain the lower sedative effects of rilmenidine.

Animals↗
PubMed2005

Imidazole binding reagent diethyl pyrocarbonate (DEPC) inhibits avian intrapulmonary chemoreceptor discharge in vivo.

Data indicate that avian intrapulmonary chemoreceptors (IPC) transduce CO2 stimuli by sensing the products of CO2 hydration, [H+] and [HCO3-]. The alphastat regulation hypothesis of physiological pH sensitivity suggests that proteins sense [H+] through changes in the ionization state of imidazole groups (alphaIm). To test whether imidazole is involved with IPC CO2 sensitivity, we administered diethyl pyrocarbonate (DEPC) intravenously while recording from IPC exposed to varying levels of inspired CO2. At physiological pH, DEPC converts pH sensitive imidazole groups to pH-insensitive N-carbethoxyhistidyl residues. Single cell extracellular neural recordings were made from vagal filaments in anesthetized, unidirectionally ventilated Anas platyrhynchos. Without DEPC, IPC discharge rate was inversely proportional to inspired CO2 with characteristic dynamic responses to rapid CO2 alterations (n = 10). After DEPC treatment (> or = 15 mM), mean sensitivity of IPC discharge to static inspired CO2 levels was decreased 75% (P < 0.05), and mean peak dynamic IPC discharge rate was decreased 80% (P < 0.05). Additionally, we tested whether DEPC might alter IPC discharge by binding imidazole groups in the enzyme carbonic anhydrase (CA), but we found no effect on CA catalytic rate. We conclude that DEPC inhibits IPC CO2 signal transduction by modifying imidazole groups on acid-sensitive proteins other than CA, possibly membrane acid-base exchangers or ion channels. These data support the alphastat regulation hypothesis in IPC CO2 respiratory chemoreception and suggests a more direct link between H+ and membrane excitability.

Action Potentials↗
PubMed2000

Oxo-vanadium as a spin probe for the investigation of the metal coordination environment of imidazole glycerol phosphate dehydratase.

Imidazole glycerol phosphate dehydratase (IGPD) catalyses the dehydration of imidazole glycerol phosphate to imidazole acetol phosphate, an important late step in the biosynthesis of histidine. IGPD, isolated as a low molecular weight and inactive apo-form, assembles with specific divalent metal cations to form a catalytically active high molecular weight metalloenzyme. Oxo-vanadium ions also assemble the protein into, apparently, the same high molecular weight form but, uniquely, yield a protein without catalytic activity. The VO2+ derivative of IGPD has been investigated by electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR) and electron spin echo envelope modulation (ESEEM) spectroscopy. The spin Hamiltonian parameters indicate the presence of multiple 14N nuclei in the inner coordination sphere of VO2+ which is corroborated by ENDOR and ESEEM spectra showing resonances attributable to interactions with 14N nuclei. The isotropic superhyperfine coupling component of about 7 MHz determined by ENDOR is consistent with a nitrogen of coordinated histidine imidazole(s). The ESEEM Fourier-transform spectra further support the notion that the VO2+ substituted enzyme contains inner-sphere nitrogen ligands. The isotropic and anisotropic 14N superhyperfine coupling components are similar to those reported for other equatorially coordinated enzymatic histidine imidazole systems. ESEEM resonances from axial 14N ligands are discussed.

Electron Spin Resonance Spectroscopy↗
PubMed2002

Models for cytochromes c': spin states of mono(imidazole)-ligated (meso-tetramesitylporphyrinato)iron(III) complexes as studied by UV-Vis, 13C NMR, 1H NMR, and EPR spectroscopy.

A number of mono(imidazole)-ligated complexes of perchloro(meso-tetramesitylporphyrinato)iron(III), [Fe(TMP)L]ClO(4), have been prepared, and their spin states have been examined by (1)H NMR, (13)C NMR, and EPR spectroscopy as well as solution magnetic moments. All the complexes examined have shown a quantum mechanical spin admixed state of high and intermediate-spin (S = 5/2 and 3/2) states though the contribution of the S = 3/2 state varies depending on the nature of axial ligands. While the complex with extremely bulky 2-tert-butylimidazole (2-(t)()BuIm) has exhibited an essentially pure S = 5/2 state, the complex with electron-deficient 4,5-dichloroimidazole (4,5-Cl(2)Im) adopts an S = 3/2 state with 30% of the S = 5/2 spin admixture. On the basis of the (1)H and (13)C NMR results, we have concluded that the S = 3/2 contribution at ambient temperature increases according to the following order: 2-(t)BuIm < 2-(1-EtPr)Im < 2-MeIm <or= 2-EtIm <or= 2-(i)PrIm < 4,5-Cl(2)Im. The effective magnetic moments determined by the Evans method in CH(2)Cl(2) solution are 5.9 and 5.0 mu(B) at 25 degrees C for [Fe(TMP)(2-(t)BuIm)]ClO(4) and [Fe(TMP)(2-MeIm)]ClO(4), respectively, which further verify the order given above. Comparison of the NMR and EPR data has revealed that the S = 3/2 contribution changes sensitively by the temperature; the S = 3/2 contribution decreases as the temperature is lowered for all the mono(imidazole) complexes examined in this study. The solvent polarity also affects the spin state; polar solvents such as methanol and acetonitrile increase the S = 3/2 contribution while nonpolar solvents such as benzene decrease it. These results are explained in terms of the structurally flexible nature of the mono(imidazole) complexes; structural parameters such as the Fe(III)-N(axial) bond length, displacement of the iron from the N4 core, tilting of the Fe(III)-N(axial) bond to the heme normal, orientation of the coordinated imidazole ligand, etc., could be altered by the nature of the axial ligands as well as by the solvent polarity and temperature. Some mysteries on the spin states of cytochromes c' isolated from various bacterial sources are possibly explained in terms of the flexible nature of the mono(imidazole)-ligated structure.

Journal Article↗
PubMed2003

Induced fit process in the selective distal binding of imidazoles in zinc(II) porphyrin receptors.

The respective affinities of various imidazole derivatives, imidazole (ImH), 2-methylimidazole (2-MeImH), 2-phenylimidazole (2-PhImH), N-methylimidazole (N-MeIm), 2-methylbenzimidazole (2-MeBzImH), and 4,5-dimethylbenzimidazole (4,5-Me(2)BzImH), for two phenanthroline (Phen) strapped zinc(II) porphyrin receptors porphen-Zn 1-Zn and 2-Zn have been studied. The formation of a supplementary H-bond considerably enhances the affinity of the zinc(II)-porphen receptor for imidazoles unsubstituted on the pyrrolic nitrogen (ImH) versus N-substituted imidazoles such as N-MeIm. The ImHs subset porphen-Zn complexes are formed with association constants up to 4 orders of magnitude superior to those measured either for N-MeIm as substrate or TPP-Zn as receptor. Distal or proximal binding of the substrates was determined by (1)H NMR measurements and titration. In two cases, the very high stability of the inclusion complex enabled the use of 2D NMR techniques. Excellent correlation between solution and solid-state structures has been obtained. A total of six X-ray structures are detailed in this article showing that the evolution of the shape of the zinc(II) receptor is mostly dependent on the steric constraints induced by the substitution on the imidazole. Hindered guests also progressively induce considerable mobility restrictions and severe distortions on the receptor, especially in the case of 2-MeBzImH and 2-PhImH.

Journal Article↗
PubMed2003

A new family of spin crossover complexes with a tripod ligand containing three imidazoles: synthesis, characterization, and magnetic properties of [FeIIH3LMe](NO3)2.1.5H2O, [FeIIILMe].3.5H2O, [FeIIH3LMe][FeIILMe]NO3, and [FeIIH3LMe][FeIIILMe](NO3)2 (H3LMe) = Tris[2-(((2-methylimidazol-4-yl)methylidene)amino)ethyl]amine).

A new family of spin crossover complexes, [Fe(II)H(3)L(Me)](NO(3))(2).1.5H(2)O (1), [Fe(III)L(Me)].3.5H(2)O (2), [Fe(II)H(3)L(Me)][Fe(II)L(Me)]NO(3) (3), and [Fe(II)H(3)L(Me)][Fe(III)L(Me)](NO(3))(2) (4), has been synthesized and characterized, where H(3)L(Me) denotes a hexadentate N(6) tripod ligand containing three imidazole groups, tris[2-(((2-methylimidazol-4-yl)methylidene)amino)ethyl]amine. It was found that the spin and oxidation states of the iron complexes with this tripod ligand are tuned by the degree of deprotonation of the imidazole groups and by the 2-methyl imidazole substituent. Magnetic susceptibility and Mössbauer studies revealed that 1 is an HS-Fe(II) complex, 2 exhibits a spin equilibrium between HS and LS-Fe(III), 3 exhibits a two-step spin transition, where the component [Fe(II)L(Me)](-) with the deprotonated ligand participates in the spin transition process in the higher temperature range and the component [Fe(II)H(3)L(Me)](2+) with the neutral ligand participates in the spin transition process in the lower temperature range, and 4 exhibits spin transition of both the Fe(II) and Fe(III) sites. The crystal structure of 3 consists of homochiral extended 2D puckered sheets, in which the capped tripodlike components [Fe(II)H(3)L(Me)](2+) and [Fe(II)L(Me)](-) are alternately arrayed in an up-and-down mode and are linked by the imidazole-imidazolate hydrogen bonds. Furthermore, the adjacent 2D homochiral sheets are stacked in the crystal lattice yielding a conglomerate as confirmed by the enantiomeric circular dichorism spectra. Compounds 3 and 4 showed the LIESST (light induced excited spin state trapping) and reverse-LIESST effects upon irradiation with green and red light, respectively.

Journal Article↗
PubMed1986

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones.

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.

Animals↗
PubMed1999

Binding of AR-1-144, a tri-imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy.

The interactions of N-[2-(dimethylamino)ethyl]-1-methyl-4-[1-methyl-4-[4-formamido-1-meth ylimidazole-2-carboxamido]imidazole-2-carboxamido]imidazole-2-c arboxa mide (AR-1-144), a tri-imidazole polyamide minor groove binder, with DNA have been investigated by NMR and CD spectroscopy. A series of DNA oligonucleotides with a C/G-containing four-bp core, i.e. CCGG, CGCG, GGCC, and GCGC, have been titrated with AR-1-144 at different ratios. AR-1-144 favors the CCGG sequence. The flanking sequence of the CCGG core also influences the binding preference, with a C or T being favored on the 3'-side of the CCGG core. The three-dimensional structure of the symmetric 2:1 side-by-side complex of AR-1-144 and GAACCGGTTC, determined by NOE-constrained NMR refinement, reveals that each AR-1-144 binds to four base pairs, i.e. at C5-G6-G7-T8, with every amide-imidazole unit forming two potential hydrogen bonds with DNA. The same DNA binding preference of AR-1-144 was also confirmed by circular dichroism spectroscopy, indicating that the DNA binding preference of AR-1-144 is independent of concentration. The cooperative binding of an AR-1-144 homodimer to the (purine)CCGG(pyrimidine) core sequence appears to be weaker than that of the distamycin A homodimer to A/T sequences, most likely due to the diminished hydrophobic interactions between AR-1-144 and DNA. Our results are consistent with previous footprinting data and explain the binding pattern found in the crystal structure of a di-imidazole drug bound to CATGGCCATG.

Base Sequence↗