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PubMedDate not supplied

Imidazole antimycotics: selective inhibitors of steroid aromatization and progesterone hydroxylation.

Econazole, imazalil, and prochloraz, which have broad spectrum antimycotic activity, are shown to be potent inhibitors of steroid aromatase activity of human placental microsomes. The IC50 values for the inhibition of aromatase activity by econazole, imazalil, miconazole, prochloraz, clotrimazole, ketoconazole, and aminoglutethimide are 0.03, 0.15, 0.6, 0.7, 1.8, 60, and 45 microM, respectively. Econazole and 4-hydroxyandrostenedione also inhibit the steroid aromatase activity of human fetal liver, a finding which suggests that extraplacental aromatase may have many similarities to the placental enzyme. Econazole is a more effective inhibitor of placental aromatization of 19-hydroxyandrostenedione than of androstenedione. This observation is consistent with the competitive nature of the inhibition of aromatase by imidazole antimycotic agents and the reduced affinity of the placental aromatase enzyme for 19-hydroxyandrostenedione compared to androstenedione. The effectiveness of these imidazole antimycotic agents to inhibit the multiple hydroxylations of progesterone which are catalyzed by human fetal adrenal microsomes is also defined. While all of the imidazole antimycotic agents are potent inhibitors of the 16 alpha-, 17 alpha-, and 21-hydroxylations of progesterone, selective inhibitory profiles are apparent. Ketoconazole is a most potent inhibitor of human fetal adrenal progesterone 16 alpha- and 17 alpha-hydroxylases while clotrimazole and imazalil are the most potent inhibitors of progesterone 21-hydroxylase. These results are strongly supportive that imidazole drugs are selective inhibitors not only of steroid aromatase but also of other microsomal steroid hydroxylases.

Adrenal Glands↗

PubMed1978

A comparison of imidazole and 9,11-azoprosta-5,13-dienoic acid. Two selective thromboxane synthetase inhibitors.

Two selective thromboxane A2 synthetase inhibitors, imidazole and 9,11-azoprosta-5,13-dienoic acid (azo analog I) were compared to determine their effects on the quantitative formation of thromboxane B2 and prostaglandin E2 accompanying human platelet aggregation. Azo analog I was at least 200 times more potent, on a molar basis, than imidazole in suppressing thromboxane B2 formation in either platelet-rich plasma or washed platelet suspensions aggregated with arachidonic acid or prostaglandin H2. The inhibitors differed in their effect on the aggregation response itself. Azo analog I selectively suppressed thromboxane A2 formation with an accompanying, parallel, suppression of the platelet aggregation. Imidazole selectively suppressed thromboxane A2 formation, but only suppressed the accompanying aggregation in platelet rich plasma, and not washed platelet suspensions. The results indicate that azo analog I functions by competitive inhibition of prostaglandin H2 on the thromboxane synthetase, and that imidazole, while it suppresses thromboxane A2 formation, may have an associated agonist activity that enhances platelet aggregation. The data presented support this hypothesis, and they emphasize the importance of thromboxane A2 in arachidonate mediated platelet aggregation.

Arachidonic Acids↗

PubMed1991

Human blood platelet alpha adrenoceptor in view of the effects of various imidazol(in)e drugs on aggregation.

1. Sixteen imidazol(in)e derivative drugs were tested with regards to their aggregatory and antiaggregatory effects on human blood platelets. 2. Platelet aggregation in response to fixed concentrations of the agents was quantified by the turbidimetric method of Born. 3. Inhibitory effects of the imidazol(in)es against the epinephrine (10(-5) M) induced aggregation was related to concentration of the agents. Of the compounds studied, UK 14,304 elicited an aggregatory effect of a magnitude similar to epinephrine. 4. A strong aggregatory agent appeared also moxonidine. 5. Small aggregation was observed in response to clonidine, antazoline and tetryzoline. 6. For all the group of imidazol(in)e drugs, excepting UK 14,304 and moxonidine, a significant inhibition of the epinephrine induced aggregation was noted. 7. Analysing inhibitory activity of imidazol(in)es one notes the drugs commonly assumed to interact with alpha 2 adrenoceptor among the most potent inhibitors, and those classified as alpha 1 adrenoceptor agonists among the less active agents. 8. The results here obtained suggest some similarity between the platelet adrenoceptor and the alpha 2 subtype of adrenoceptor identified in human circulatory system. 9. Differences appear between the two types of receptors and the existence of a separate alpha 3 class of adrenoceptors in human blood platelets should be considered.

Blood Platelets↗

PubMed2005

Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel Capravirine analogues.

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-imidazol-2-ylthio)acetamide (3a-c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio]acetate (10), 2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamides (12a-f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-isopropyl-1H-imidazol-2-ylthio]acetamides (14a-l) from their corresponding amino acids through a sequence of reactions: Dakin-West reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found active.

Anti-HIV Agents↗

PubMed1986

Chemical reclosure of opened imidazole ring of guanine.

Imidazole ring opened adenine and guanine residues similar to those generated by gamma-irradiation of nucleosides of DNA, were chemically synthesised. Reaction conditions that promote the chemical reclosure of opened imidazole rings of guanine have been identified. The optimal conditions for the reclosure of such rings was found to be 0.2 M HCl at 37 degrees C. These conditions did not promote a reclosure of opened imidazole rings of adenine. The reclosure of opened imidazole rings of guanine was found to follow first order kinetics. The very low pH for this chemical ring reclosure precludes the likelihood that this reaction occurs intracellularly.

Adenine↗

PubMed2002

Synthesis of oxathiolane imidazole nucleosides.

Nucleosides have been of great interest since their strong antiviral activities were discovered. 1,3-Oxathiolane ring system has been known for many years, but it is in recent years that the ring has been used as the sugar ring in nucleoside analogs (Synthesis (1991) 1046; J. Am. Chem. Soc. 113 (1991) 9377; Tetrahedron Lett. 35 (1994) 4739). Besides, bredinin is a natural nucleoside antibiotic with imidazole moiety and there are some other studies reported on nucleosides with the imidazole group (Biorg. Med. Chem. 7 (1999) 481; Biorg. Med. Chem. 7 (1999) 1617; Nucleosides Nucleotides 18 (1999) 331). These findings make the imidazole group interesting as the base of a nucleoside. In this study, in order to find out the structure-activity relationships of L-oxathiolanyl nucleosides, L-oxathiolanyl imidazole nucleosides 7 and 8 were synthesized, via novel intermediates 2-6, which were then tested for anti-HIV activity (Antivir. Res. 1-11 (1994) 25) in human peripheral blood mononuclear (PBM) cells, the synthesized nucleosides did not show significant activity up to 100 microM against HIV-1.

Anti-HIV Agents↗

PubMed1985

Do the imidazoles have a role in the management of genitourinary fungal infections?

The imidazoles have demonstrated antifungal activity against a number of fungi that are pathogenic for man. Effective clinical use has been demonstrated in patients with cutaneous and systemic candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, cryptococcus and systemic candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, cryptococcus and histoplasmosis. We report our experience with the oral imidazole agent ketoconazole in the management of 8 patients with significant urinary candidiasis as judged by elevated urinary candidal counts (greater than 15,000/ml.). Only 4 of the 8 patients had resolution of candiduria with ketoconazole therapy. Intravenous miconazole, another imidazole, has been available for treatment of systemic and genitourinary fungal infections. Limited success (50 per cent) with intravenous miconazole has been noted in the treatment of systemic candidiasis with urinary involvement. Miconazole also has been used as a systemic and local irrigant in the treatment of bladder and renal candidiasis. Based on these observations and our own studies, we believe that the imidazoles have a limited role in the management of patients with significant fungal involvement of the urinary tract.

Adult↗

PubMed1979

Comparison of procarbazine, imidazole-carboxamide and cyclophosphamide in relapsing patients with advanced carcinoma of the prostate.

In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed, relapsing clinical stage D prostatic cancer were randomized to receive either imidazole-carboxamide, procarbazine or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on initial therapy were crossed over or randomized to receive an alternate drug. There were 129 patients available for comparison of treatments. The objective response rates (partial regression plus stable disease) were 26% for cyclophosphamide, 27% for imidazole-carboxamide and 14% for procarbazine. Subjective responses were noted in pain relief, improvement in performance status and weight gain. Procarbazine was associated with excessive toxicity, resulting in many patients (28%) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study. The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival. Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease.

Aged↗

PubMed2000

Speciation in vanadium bioinorganic systems. 6. Speciation study of aqueous peroxovanadates, including complexes with imidazole.

Using a combination of potentiometry (glass electrode) and quantitative 51V NMR spectroscopy, the full speciation in the vanadate-peroxide and vanadate-peroxide-imidazole systems was determined in the pH range 1-10 (0.150 M Na(Cl) medium, 25 degrees C). Using the computer program LAKE, the pKa value of imidazole and the formation constants for 10 peroxovanadate species and also for three more species where a single imidazole moiety is also bound, have been calculated. The experimental data show a good fit to the calculated speciation model, even for the less abundant species. The species are either monomeric or dimeric in vanadium, and four resonances of the dimeric species have been unambiguously assigned via 2D 51V NMR. Diperoxovanadates are the favoured species at pH 2-10, when sufficient peroxide is present. Imidazole is found to bind strongly to them at pH 6-9. The equilibrium conditions are illustrated in distribution diagrams.

Hydrogen Peroxide↗

PubMed1981

A comparison of the binding of imidazole to valence hybrid and methemoglobin: an assignment of individual heme reactivity.

The ferric hemes of valence hybrid hemoglobins combine with imidazole in a manner analogous with the hemes of methemoglobin. Equilibrium studies show that imidazole binding to methemoglobin is minimally described by the sum of two independent processes (k1 = 200 M-1 an K2 = 37 M-1), both of which contribute equally to the observed difference spectrum. Using valance hybrid hemoglobins, which show single binding processes under similar conditions, it is possible to identify the high affinity sites in methemoglobin with the alpha chains and the low affinity sites with the beta chains. Kinetic studies show that the valance hybrid hemoglobins react in a single exponential fashion with imidazole in contrast with methemoglobin which shows a biphasic reaction (k1 = 85 M-1 sec-1 k2 = 25 M-1 sec-1). A comparison of the rates of reaction of the hybrids allows the assignment of the fast phase in methemoglobin to the beta chains and the slow phase to the alpha chains. The heterogeneity of the imidazole reaction with methemoglobin occurs over the pH range 5.5-9.5 within which two ionization processes are discernable at pH 6.9 an 7.5.

Adult↗

PubMed1998

Site-specific cleavage of tRNA by imidazole and/or primary amine groups bound at the 5'-end of oligodeoxyribonucleotides.

Sequence specific RNA cleaving molecules were synthesized by attaching novel polyamine derivatives bearing imidazole and/or primary amine groups to the 5'-end of DNA oligonucleotides as the sequence-recognizing moieties. The actions of the molecules on a half-tRNA(Asp) were investigated. The oligonucleotides directed the nuclease activity (the imidazole and the primary amine are the catalytic groups) of the enzyme to the nucleotides directly adjacent to the complementary target sequence on the substrate RNA. The cleavage reaction shows a bell-shaped pH dependence with a maximum at pH 7.0, indicating the participation of protonated and non-protonated imidazoles residues in the process. The specificity of these hybrid enzymes can be easily altered, and they should prove to be useful tools for probing RNA structures in solution and as potential reactive groups in antisense oligonucleotide derivatives. We also describe the site-specific cleavage of tRNA(Asp) by the cleaving reagents bearing imidazole and/or primary amine groups at the 5'-end of oligodeoxyribonucleotides.

Amines↗

PubMed2000

Propyl gallate increases in vitro antifungal imidazole activity against Candida albicans.

We looked at the in vitro effect of an antioxidant, propyl gallate (PG), on the antifungal activity of miconazole sulphosalicylate, econazole sulphosalicylate and ketoconazole against 40 clinical isolates of Candida albicans. The combination of imidazole and PG gave MIC values 10-150 times lower than those of imidazole alone. The optimal conditions for this enhanced activity were pH 6.2-8.0 and a fungal cell concentration lower than 3 x 10(5) cells/ml. The mechanism of the interaction between imidazole and PG is not known but may be as a result of an effect of PG on the P-450 cytochrome. Theoretically this combination could reduce the side effects of long treatment with imidazoles and lower the risk of resistance to these antifungal drugs.

Antifungal Agents↗

PubMed1996

Imidazole fungicides provoke histamine release from mast cells and induce airway contraction.

The effects of imidazole fungicides on rat mast cells and on guinea-pig airway smooth muscle contraction were studied. The dose-effect studies on mast cells were performed to prove our hypothesis that imidazole fungicides are potential histamine releasing agents and thus may induce bronchoconstriction in vivo. Indeed, all imidazole fungicides tested (i. e. ketoconazole, miconazole, prochloraz) and an agricultural formulation of prochloraz (i. e. Sportak) were able to elicit histamine release from mast cells in the concentration range of 30-300 microM, although there were marked differences in potency and efficacy. The in vivo experiments clearly showed that inhaled Sportak aerosols induce a significant bronchoconstriction in guinea-pigs. Moreover, after a single 5 min exposure to Sportak aerosols the animals developed airway hyperreactivity against histamine. From the results of our study it may be concluded that certain imidazole fungicides provoke histamine release by a non-immunological mechanism, induce airway constriction in guinea-pigs and hence may be harmful to spray operators who might inhale fungicide aerosols used for plant protection.

Animals↗

PubMed2000

The electronic structure and spectra of Ru(II) and Ru(III) complexes with imidazole and its derivatives.

The calculations of the electronic structure and spectra of [Ru(NH3)5L]2+ (L = imidazole, histidine) and [Ru(NH3)5L]3+ (L = imidazole, N-imidazolate anion, 4-methylimidazole, 4-methyl-1N-imidazolate anion and 1N-bound histidine) complexes are performed in the framework of the CI method in the INDO/CNDO approximation. The MO diagram is obtained. The assignment of all transitions with energies of 4-5 eV is made and the nature of corresponding excited states is discussed. For the Ru(II) complexes, the lower energy observable transition is assigned to d-->pi* type, whereas the higher energy one is assigned to pi-->pi* type. In the spectra of the Ru(III) complexes with charged ligands both transitions are of pi-->d character, while in the case of uncharged ligands, the higher energy transition mostly incorporates pi-->pi* excitations.

Histidine↗

PubMed2003

Evaluation of chromatographic recycling for imidazole used in the chromatographic purification of His-tag recombinant proteins.

The aim of this work was to test a recycling method for imidazole used in immobilized metal affinity chromatography (IMAC) as eluent for recombinant histidine-tag (His-tag) protein. After evaluating two supports, the method was optimized with a mixture of bovine serum albumin, sodium chloride and imidazole. Recycling was performed with an eluate fraction from IMAC of His-tag enhanced green fluorescent protein produced in our laboratory and pure imidazole was recovered in water and was analyzed after being freeze-dried. The imidazole was then reused as eluent in IMAC without any modification in its structure or behavior. This procedure can be used for large-scale chromatography.

Chromatography, Affinity↗

PubMed1985

Effect of pH on oxidation-reduction potentials of 8 alpha-N-imidazole-substituted flavins.

The pKa values for the various ionic forms of 8 alpha-N-imidazolylriboflavin were determined in its oxidized and hydroquinone forms and estimated for its semiquinone form. The pH dependence of the absorption and fluorescence spectral properties and potentiometric titration data show the pKa values for the oxidized form to be 6.02 +/- 0.03 for the 8 alpha-imidazole nitrogen and 9.67 +/- 0.05 for the N(3) position of the flavin ring. The pH dependence of the oxidation-reduction potential was determined by spectrocoulometric titrations, and the data points were compared with computer-simulated plots. Two pKa values for the hydroquinone form of the flavin were determined and assigned. The pKa for the imidazole ring is found to be 6.9 +/- 0.1 and for the N(1) position of the flavin hydroquinone is found to be 5.5 +/- 0.1. Analysis of the pH dependence of the one-electron couples E2 (flavoquinone/flavin semiquinone, Flox/Fl.) and E1 (flavin semiquinone/flavin hydroquinone, Fl./Flred) resulted in an estimated pKa of 6.5 for the 8 alpha-imidazole ring in the flavin semiquinone form. These data show the possible involvement of the ionization of the 8 alpha-imidazole substituent in the redox chemistry of flavoenzymes containing either an 8 alpha-N1- or an 8 alpha-N3-histidyl-linked covalent flavin coenzyme. Future work on oxidation-reduction potentials of this class of enzymes must take into consideration the influence of the 8 alpha-histidyl substituent.

Chemical Phenomena↗

PubMed1987

Influence of 8 alpha-imidazole substitution of the FMN cofactor on the rate of electron transfer from the neutral semiquinones of two flavodoxins to cytochrome c.

The effects of substituting an imidazole ring onto the 8 alpha-position of the FMN cofactor on the kinetics of electron transfer from the neutral semiquinone forms of Azotobacter and Clostridium flavodoxins to oxidized horse heart cytochrome c have been investigated by stopped-flow methods. Although 8 alpha-substitution does not alter the mechanistic pathway of the reaction, the rate constants are decreased by factors of 10-30, without significant changes in the equilibrium association constants of the intermediate electron-transfer complexes. Protonation of the imidazole ring further decreases the observed second-order rate constants for the electron-transfer reaction by factors of 20-50. The pKa values for the 8 alpha-imidazole ring in both flavodoxin semiquinones were determined to be approximately 7. In contrast, the reactions of the native flavodoxins with cytochrome c are pH independent. The results are consistent with a structural model of the intermediate complex [Simondsen, R. P., Weber, P. C., Salemme, F. R., & Tollin, G. (1982) Biochemistry 21, 6366-6375], which postulates a close fit between the exposed dimethylbenzene ring of the FMN and the heme edge within a nonpolar interface region. The results further indicate that electron transfer is uncoupled from proton transfer, that it is the rate-limiting step, and that it occurs prior to proton transfer at all pH values. Finally, the results do not provide support for a direct role of the imidazole ring in the facilitation of one-electron transfer in those enzymes containing 8 alpha-N-histidylflavin coenzymes.

Clostridium↗

PubMed1977

Interaction of the unique competitive inhibitor imidazole with human carbonic anhydrase B.

Imidazole was previously found to be unique among the inhibitors of human carbonic anhydrase B (HCAB) in that it binds competitively with the CO2 substrate (Khalifah, R. G. (1971), J. Biol. Chem. 246, 2561). We report here an aromatic ultraviolet difference spectral study of its interaction with HCAB and compare it with a variety of other inhibitors. Imidazole is found to be unique in that: (1) it generates a different spectrum upon binding that is also much supressed in intensity; (2) its affinity for HCAB is maximal at high pH, being abolished upon its protonation and being independent of active-site ionizations. Imidazole differs from CO2 in that it binds competitively with the anionic inhibitor iodide. The unique properties of imidazole binding are consistent with the recently determined crystal structure of its complex with HCAB showing it to bind as a weak and distant fifth ligand of the essential zinc atom, rather than displacing the solvent molecule in the fourth ligand position (Kannan, K.K., Petef, M., Fridborg, K., Cid-Dresdner, H., and Lövgren, S. (1977), FEBS Lett 73, 115).

Binding, Competitive↗