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PubMed1991

Gas chromatographic-mass spectrometric determination of two new antimycotic agents, 1-[(5-chloro-2-benzofuranyl)(2-chlorophenyl)methyl]-1H-imidazole and 1-[(5-bromo-2-benzofuranyl)phenylmethyl]-1H-imidazole, in rabbit plasma following topical administration: a preliminary comparison with bifonazole.

A method for the analysis of the antimycotic drugs 1-[(5-chloro-2-benzofuranyl)(2-chlorophenyl)methyl]-1H-imidazole, 1-[(5-bromo-2-benzofuranyl)phenylmethyl]-1H-imidazole and bifonazole in rabbit plasma, employing gas chromatography-mass spectrometry with selected-ion monitoring, was developed. The procedure involved single-step purification of the biological matrix via liquid-liquid extraction on Extrelut columns and use of a carrier substance to minimize the negative effects of adsorption sites during the gas chromatographic process. The limits of detection ranged from 0.1 to 1.4 ng/ml, starting from a 200-microliter sample. The method was applied to a preliminary evaluation of percutaneous absorption of both drugs in the rabbit after a single administration, in comparison with bifonazole.

Administration, Topical↗
PubMed2006

EPR and HYSCORE investigation of the electronic structure of the model complex Mn(imidazole)6: exploring Mn(II)-imidazole binding using single crystals.

The electronic structure of the Mn(II)-imidazole binding was studied by EPR spectroscopy using the model complex Mn(Im)(6) diluted in a single crystal of Zn(Im)(6)Cl(2).4(H(2)O). The second rank zero-field splitting (ZFS) tensor (D tensor) of the two sites, a and b, present in the crystal was determined by measuring the orientation patterns of the echo-detected EPR spectra in three different planes at 10K (D(a)=-106, D(b)=-118, E(a)=-17, E(b)=-22x10(-4)cm(-1). Euler angles with respect to the crystal habitus: alpha(a)=13 degrees , beta(a)=76 degrees , gamma(a)=108.5 degrees , alpha(b)=14 degrees , beta(b)=73.5 degrees , gamma(b)=103.5 degrees ). The contribution of cubic ZFS terms to the spectrum allowed us to determine the orientation of the N-Mn-N directions of the complex as well (Euler angles in the D tensor reference frame alpha=100 degrees , beta=23 degrees , gamma=0 degrees , both centers having the same orientation). The hyperfine interactions with (14)N were explored by HYSCORE spectroscopy. The correlation patterns and modulation amplitudes in the 2D experiments were studied for different electron spin transitions and orientations of the crystal. Signals of three different pairs of nitrogens were found. The results were analyzed considering that the N-Mn binding directions are principal directions of the hyperfine and nuclear quadrupole tensor of (14)N. All three pairs of nitrogens were found to be almost equivalent with an isotropic contribution of A(iso) approximately 3.2MHz and an almost axial anisotropic coupling of 2T approximately 1.1MHz along the N-Mn bonding direction. The nuclear quadrupole principal values are 1.5MHz along the bonding direction, -0.6MHz in the direction perpendicular to the imidazole plane, and -0.9MHz in the direction perpendicular to both.

Algorithms↗
PubMed2003

Synthesis and antimicrobial properties of 3-aryl-1-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-yl)propanes as 'carba-analogues' of the N-arylmethyl-N-[(1,1'-biphenyl)-4-ylmethyl])-1H-imidazol-1-amines, a new class of antifungal agents.

A new series of 3-phenyl-1-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-yl)propane derivatives 2a-l (related to the antifungal bifonazole) was synthesized and tested for antimicrobial activity. A number of substituents on the phenyl ring were chosen to compare the relative biological properties with those of corresponding aza-analogues, previously described by us. The in vitro antifungal activities of the newly synthesized azoles were tested against several pathogenic fungi responsible for human disease. Test pathogens included representatives of yeasts (Candida albicans, Candida parapsilosis, Criptococcus neoformans), dermathophytes (Tricophyton verrucosum, Tricophyton rubrum, Microsporum gypseum) and moulds (Aspergillus fumigatus). Bifonazole and miconazole were used as reference drugs. Title compounds were prepared by alkylation of 1-biphenyl-4-yl-2-imidazol-1-yl-ethanone with the proper arylmethyl halide and subsequent reduction of corresponding ketones applying the Huang-Minlon modification of the Wolff-Kishner reaction.

Amines↗
PubMed2000

Effects of 2-(substituted-sulfanyl)-3,5-dihydro-imidazole-4-one and 2-(substituted-sulfanyl)-1H-imidazole-4,5-dione derivatives on serum HDL-cholesterol.

A series of 2-substituted sulfanyl-3,5-dihydro-imidazole-4-ones and 2-substituted sulfanyl-1H-imidazole-4,5-diones was prepared and shown to increase high density lipoprotein cholesterol over other lipid fractions. Compound 1f showed efficacy in additional animal models. The major metabolite of 1f was isolated and its synthesis is reported. The effects of the metabolite on the lipid profile in rats were investigated.

Animals↗
PubMed1993

Mutagenic and genotoxic effects of three vinyl chloride-induced DNA lesions: 1,N6-ethenoadenine, 3,N4-ethenocytosine, and 4-amino-5-(imidazol-2-yl)imidazole.

The mutagenic and genotoxic properties of 1,N6-ethenoadenine (epsilon Ade), 3,N4-ethenocytosine (epsilon Cyt), and 4-amino-5-(imidazol-2-yl)imidazole (beta) were investigated in vivo. The former two modified bases are known DNA adducts formed by the human carcinogen vinyl chloride; beta is formed by pyrimidine ring-opening of epsilon Ade. Chemically synthesized deoxyhexanucleotides containing epsilon Ade and beta, d[GCT-(epsilon A)GC], and d[GCT(beta)GC], respectively, were described previously [Biochemistry (1987) 26, 5626-5635]. epsilon Cyt was inserted into an oligonucleotide, d[GCTAG(epsilon C)], by a mild enzymatic synthetic procedure, which avoided exposure of the base to alkaline conditions. 3,N4-Etheno-2'-deoxycytidine 3',5'-bisphosphate coupled with reasonable efficiency (30-40%) to the 3'-nucleoside of an acceptor pentamer, d(GCTAG), in a reaction catalyzed by T4 RNA ligase in the presence of ATP. Each of the three modified hexanucleotides and an unmodified control were inserted into a six-base gap positioned at a known site in the genome of bacteriophage M13-NheI. A nick was placed in the DNA strand opposite that containing the single DNA lesions, enabling the formation of singly adducted single-stranded genomes by denaturation. After transfection of the adducted phage DNAs into Escherichia coli, each of the adducts was found to be genotoxic. The most toxic lesion was beta, which reduced survival of the genome by 97%. epsilon Cyt and epsilon Ade reduced survival by 90% and 65%, respectively. An examination of the surviving phage populations revealed that each of the three adducts was mutagenic. The least mutagenic lesion was epsilon Ade (0.1% of the survivors were mutant), which showed primarily A-->G transitions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗
PubMed1981

Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.

The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.

Animals↗
PubMed1977

Antimycotic imidazoles. 2. Synthesis and antimycotic properties of 1-[2-(arylalkyl)-2-phenylethyl]-1H-imidazoles.

Synthesis of 1-[2-(arylalkyl)-2-phenylethyl]-1H-imidazoles was accomplished starting from the corresponding phenylacetonitriles. Via successive alkylation, conversion to the corresponding ester, and sodium borohydride-lithium iodide reduction, beta-phenylalcanols were obtained. These alcohols were mesylated and then refluxed with imidazole in dimethylformamide to yield the title compounds, which were active in vitro against dermatophytes, yeasts, other fungi, and gram-positive bacteria. Some were also active in vivo against Candida albicans.

Animals↗
PubMedDate not supplied

Structure-activity relationship studies of CNS agents. Part VII. The effect of the imidazole fragment in 2-substituted 1-[3-(4-aryl-1-piperazinyl)propyl]imidazoles on their interaction modes with 5-HT1A and 5-HT2 receptors.

The synthesis and the 5-HT1A and 5-HT2 receptor affinity of 2-substituted 1-[3-(4-aryl-1-piperazinyl)propyl]-imidazoles (1-8) has been described. It has been shown that both the N-3 imidazole atom and the N-1 piperazine one should be considered as possible protonation centers under physiological conditions. It has been found that the folded conformations of 1-8 exist predominantly in solution. Moreover, three different modes of interaction of the analyzed compounds with 5-HT1A and 5-HT2 receptor sites have been proposed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Accumulation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-aminodipyrido[1,2-a:3',2'-d]imidazole, carcinogenic glutamic acid pyrolysis products, in plasma of patients with uremia.

In order to investigate the exposure of humans to 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole [(Glu-P-1) Chemical Abstracts Service:67730-11-4] and 2-aminodipyrido[1,2-a:3',2'-d]imidazole [(Glu-P-2) Chemical Abstracts Service:67730-10-3], carcinogenic heterocyclic amines, we developed a high-performance liquid chromatography method to detect Glu-P-1 and Glu-P-2 in biological samples, and compared the plasma levels of the carcinogens in normal subjects with those in uremic patients in which higher incidence of malignancy has been reported. Glu-P-1 and Glu-P-2 levels in plasma of uremic patients before induction of hemodialysis treatment were 12.62 +/- 3.65 (SD) pmol/ml (n = 5) and 14.81 +/- 5.17 pmol/ml (n = 5), respectively, whereas Glu-P-1 and/or Glu-P-2 could be detected in only two of seven normal subjects and the levels were lower than 3.1 pmol/ml. Approximately 10% of these carcinogens in plasma of uremic patients could be removed by the first hemodialysis treatment, and reasonable amounts of these carcinogens could be detected in the dialysate of uremic patients. However, significant amounts of Glu-P-1 and Glu-P-2 were still detected in plasma of all uremic patients even after 1 month-hemodialysis treatments. These results suggest that one of the excretory pathways of these carcinogens is via kidney.

Adult↗
PubMed1986

Inhibition of thromboxane synthetase by the imidazole derivative 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid as a novel therapeutic approach to experimental myocardial ischemia.

3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK 38.485), a novel imidazole derivative, was employed to study potential protective effects of thromboxane synthetase inhibition on ischemically stressed canine myocardium. In anaesthetized open-chest mongrel dogs (n = 5) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the left anterior descending artery. A total of 18 occlusions after therapy was analysed and compared to a total of 15 occlusions under control conditions. In each experiment 2-3 control occlusions and 3-4 occlusions under therapy were performed. The drug was applicated intravenously at a dose of 5 mg/kg body weight 30 min before the first therapy occlusion. Hemodynamics and energetics did not significantly change. The efficiency of the drug in protecting ischemically stressed myocardium was examined by the amounts of potassium, inorganic phosphate and lactate released in the first minute of reperfusion and by quantification of 02-debt and 02-repayment in the occlusion and reperfusion periods. Compared to control occlusions, premedication with UK 38.485 led to a reduced 02-debt (-39.1%; p less than 0.01) combined with a significant decrease of the release of potassium (-15.7%; p less than 0.001), inorganic phosphate (-20.2%; p less than 0.002) and lactate (-20.7%; p less than 0.01). The protective effect is suggested to be mainly due to enhanced flow to ischemic areas regarding a significant lesser reduction of myocardial blood flow and an improved oxygen uptake during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

[Durene derivates. IV. N-((2,3,5,6-tetramethylbenzoyl)alkyl)imidazoles and N-((beta-(2,3,5,6-tetramethylphenyl)-beta-hydroxy)ethyl)imidazoles with anticonvulsant activity].

A series of N-[(2,3,4,6-tetramethylbenzoyl)alkyl]imidazoles and of N-([beta-(2,3,5,6-tetramethylphenyl)-beta-hydroxy]ethyl)imidazoles has been synthesized. All compounds were tested in mice for anticonvulsant activity against electroshock and pentylenetetrazole convulsions. These durene-derivatives showed good activity, whereas the corresponding benzene-derivatives were inactive.

Animals↗
PubMed1980

Antitumor activities of newly synthesized 5-carbamoyl-1 H-imidazol-4yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4yl piperonylate.

In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.

Animals↗
PubMed1993

Bronchopulmonary actions of 1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), a substituted imidazole, in the guinea pig.

1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), was examined for bronchodilator activity in the guinea pig. In guinea pig tracheal preparations, LY150310 competitively antagonized the contractile effects of exogenous histamine and blocked the histamine-mediated component of contractions produced by ovalbumin challenge. LY150310 had little effect on the nonhistamine component of ovalbumin-induced contractions of lung parenchymal strips, but it enhanced the production of prostaglandin (PG) E2 and PGF2 alpha although it partially inhibited thromboxane B2 formation. In other studies, in which postmortem pulmonary gas trapping was used as an index of in vivo airway obstruction, i.v. LY150310 dose-dependently inhibited the bronchospasm produced by aerosols of the divalent cationic ionophore A23187, histamine, 5-hydroxytryptamine, leukotriene D4, methacholine, ovalbumin or platelet activating factor. LY150310 was equal to or more potent than aminophylline in all test systems. Also, orally administered LY150310 inhibited the airway obstruction produced by selected challenge aerosols. In ex vivo studies, LY150310 elevated PGE2 and tended to decrease thromboxane B2 in sodium arachidonate-stimulated whole blood. However, PGE2 and other cyclooxygenase products did not appear to account for in vivo bronchodilation, because combining LY150310 and piroxicam did not alter inhibition of A23187-induced airway obstruction. Our results demonstrate that LY150310 reduces airway obstruction caused by a variety of bronchoconstrictive agents, including A23187 and ovalbumin. Although this substituted imidazole appears to have activity as a histamine H1-receptor antagonist and can alter prostanoid concentrations in vitro and in vivo, its mode of bronchodilation is unclear.

Aerosols↗
PubMed1993

Imidazole based non-peptide angiotensin II receptor antagonists. Investigation of the effect of the orientation of the imidazole ring on biological activity.

Non-peptide angiotensin II receptor antagonists related to losartan (DuP 753, CAS 114798-26-4) were prepared and evaluated for antagonist activity in the rat isolated uterus assay. The synthetic strategy concentrated on changes in the orientation of the imidazole ring relative to the substituents, which were maintained in a similar pattern to that found in losartan. The results indicate that biological activity of such antagonists shows little dependence on the orientation of the imidazole ring, but that the spacing of the substituents of primary importance.

Acrylates↗
PubMed2005

Preparation of 5-amino-4-imidazole-N-succinocarboxamide ribotide, 5-amino-4-imidazole-N-succinocarboxamide riboside and succinyladenosine, compounds usable in diagnosis and research of adenylosuccinate lyase deficiency.

The enzyme adenylosuccinate lyase (ADSL) intervenes twice in the biosynthesis of adenine nucleotides. ADSL deficiency is an inherited metabolic disease characterized by various degrees of psychomotor retardation and accumulation of dephosphorylated enzyme substrates 5-amino-4-imidazole-N-succinocarboxamide riboside (SAICAr) and succinyladenosine (SAdo) in body fluids. Severity of symptoms seems to correlate with residual activity of mutant enzyme and with SAdo/SAICAr concentration ratio in cerebrospinal fluid. To better understand the pathogenetic mechanisms of the disease symptoms, studies of catalytic properties of mutant enzymes together with in vitro and in vivo experiments utilizing SAICAr and SAdo must be performed. Such studies require availability of both ADSL substrates, 5-amino-4-imidazole-N-succinocarboxamide ribotide (SAICAR) and succinyladenosine 5'-monophosphate (SAMP) and their dephosphorylated products in sufficient amounts and purity. Except for SAMP, none of these compounds is commercially available and they must therefore be synthesized. SAICAR was prepared by recombinant human ADSL-catalysed reaction of AICAR (5-aminoimidazole-4-carboxamide) with fumarate and isolated by thin-layer chromatography. SAICAr and SAdo were prepared by calf intestine alkaline phosphatase-catalysed dephosphorylation of SAICAR and SAMP and isolated on cation- and anion-exchange resin columns. The procedures described are easily scalable and provide high yields of sufficiently pure products for use in experiments related to studies of pathogenetic mechanisms in ADSL deficiency.

Adenosine↗
PubMed2001

Validated high-performance liquid chromatographic assay for simultaneous determination of dacarbazine and the plasma metabolites 5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide.

Dacarbazine (DTIC) is a prodrug that is clinically effective in the treatment of Hodgkin's disease, melanoma and soft tissue sarcoma. To better characterize the clinical pharmacology of parent drug and reactive metabolites, a reversed-phase HPLC method with UV detection was developed for simultaneous determination of dacarbazine and the metabolites 5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide (HMMTIC) and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC). Chromatographic separation was achieved with a Zorbax SB-CN column and with a mobile phase of 80% 50 mM ammonium phosphate, pH 6.5, 20% methanol and 0.1% triethylamine. HMMTIC, MTIC and DTIC were extracted from plasma with methanol precipitation of the proteins. Recovery of DTIC and the metabolites from whole blood was greater than 92%. Rapid processing of whole blood, methanol extraction and storage at -70 degrees C substantially increased the stability of HMMTIC and MTIC from less than 15 min to 3 days. Precision for HMMTIC, MTIC and DTIC ranged from 3.7 to 16.3% relative standard deviation. The accuracy ranged from 101 to 114% for all three analytes. The validated assay was used to determine the pharmacokinetic data for dacarbazine and its active metabolites for human patients with recurrent glioma receiving DTIC intravenously.

Chromatography, High Pressure Liquid↗
PubMed1992

Modification of the distal histidyl imidazole in myoglobin to N-tetrazole-substituted imidazole and its effects on the heme environmental structure and ligand binding properties.

The mechanism of N-tetrazole ring formation at the distal histidyl imidazole of sperm whale myoglobin (Mb) has been studied by nitrogen-15 (15N) NMR spectroscopy by utilizing 15N-labeled cyanogen bromide (BrCN) and azide ion (N3-). The 15N-NMR spectrum of BrC15N-modified Mb + N3- afforded two hyperfine-shifted 15N resonances, both of which are identical with the resonance positions of two of the three 15N resonances for BrCN-modified Mb + 15NN2-. This unusual spectral feature is due to the formation of the N-tetrazole ring attached to the distal histidyl imidazole and the scrambling of the labeled nitrogen originated from N3- or BrCN over the tetrazole ring upon coordination to the ferric heme iron. The ferric iron-bound N-tetrazole ring comes off upon reduction to the ferrous state, and the stable CO complex of tetrazole-modified Mb (tetrazole-Mb) is formed. Electronic absorption and 1H-NMR spectra of deoxy and carbonmonoxy forms of tetrazole-Mb are slightly altered from those of native Mb by the modification, while the most significant effect is exerted on the C-O stretching frequency of iron-bound CO. The C-O stretching band for tetrazole-MbCO is observed at 1966 cm-1 in contrast to 1945 cm-1 for native MbCO, suggesting that the geometry of iron-bound CO in tetrazole-Mb is relatively upright which is characteristic of the "open" conformer. This result corresponds to the 15-fold increase of the CO association rate constant by the N-tetrazole modification of the distal His. The oxy form of tetrazole-Mb is readily autoxidized to its ferric state, indicating that hydrogen bonding between the distal His and iron-bound oxygen is essential for stable O2 binding to the heme iron.

Animals↗
PubMed2000

2(S)-Amino-3-[1H-imidazol-4(5)-yl]propyl cyclohexylmethyl ether dihydrochloride and 2(S)-amino-3-[1H-imidazol-4(5)-yl]propyl 4-bromobenzyl ether dihydrochloride.

(Cyclohexylmethyloxymethyl)(1H-imidazol-4-iomethyl)-(S)-ammonium dichloride, C(13)H(25)N(3)O(+).2Cl(-), and (4-bromobenzyl)(1H-imidazol-4-iomethyl)-(S)-ammonium dichloride, C(13)H(18)BrN(3)O(+).2Cl(-), are model compounds with different biological activities for evaluation of the histamine H3-receptor activation mechanism. Both title compounds occur in almost similar extended conformations.

Journal Article↗