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At least 433 records · Page 24Linked to original sources
PubMed2003

Cyclophosphamide metabolism is affected by azole antifungals.

We performed a randomized trial to compare the safety and efficacy of itraconazole with fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation (SCT). Itraconazole (intravenous 200 mg daily, or oral solution 2.5 mg/kg 3 times daily) and fluconazole (intravenous or oral, 400 mg daily) were administered with the start of conditioning therapy, until at least 120 days after SCT. After enrollment of the first 197 patients, a data and safety monitoring board reviewed potential drug-related toxicities. Patients who received itraconazole developed higher serum bilirubin and creatinine values in the first 20 days after SCT, with highest values in patients who received itraconazole concurrent with cyclophosphamide (CY) conditioning. Analysis of CY metabolism in a subset of patients demonstrated higher exposure to toxic metabolites among recipients of itraconazole compared with fluconazole. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P-450 isoenzymes, affect CY metabolism and conditioning-related toxicities.

Adolescent↗
PubMed1996

Optically active antifungal azoles. VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazo l-1- yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones.

A new series of optically active antifungal azoles, N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones (1,2) and 5(1H,4H)-tetrazolones (3), were prepared from the triflate derivative of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (13) by an SN2 displacement reaction with the anion of an azolone (17-19) and subsequent ring-opening reaction with 1H-1,2,4-triazole. The optically active oxiranylethanol 13 was synthesized from methyl (R)-lactate in a stereo-controlled manner. The azolones 1-3 prepared showed potent antifungal activities in vitro and in vivo.

Antifungal Agents↗
PubMed1999

Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones.

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.

Animals↗
PubMed1999

Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]- 3(2H,4H)-1,2,4-triazolone and its analogs.

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.

Antifungal Agents↗
PubMed1998

[Anti-Candida activities of azole antifungals in the presence of lysozyme in vitro].

The combined effects of lysozyme and various antifungal agents were investigated by microbroth dilution method against Candida albicans in vitro. Synergistic anti-Candida activity was observed between egg white lysozyme and itraconazole, clotrimazole, miconazole and lanoconazole. Similar, although not as clear, combination anti-Candida activities were seen in the cases of ketoconazole, bifonazole, amphotericin B and nystatin. Anti-Candida activity of fluconazole was not affected by the addition of lysozyme, however. Physiological roles of this combination effect in anti-Candida therapy by azole antifungals were discussed.

Anti-Infective Agents↗
PubMed2000

Novel Ru(III), Rh(III), Pd(II) and Pt(II) complexes with ligands incorporating azole and pyrimidine rings. I. Antiproliferative activity in vitro.

A number of co-ordination compounds of Ru(III), Rh(III), Pd(II) and Pt(II) with ligands incorporating azole and pyrimidine rings has been synthesized. The in vitro cell proliferation-inhibitory activity of these compounds was examined against human cancer cell lines: A 549 (lung carcinoma), LS-180 (colon cancer) and MCF-7 (breast cancer), using SRB technique. Six out of 13 compounds studied revealed cytotoxic activity in vitro. Inhibitory dose 50% (ID50) was lower than 4 microg/ml, which is an activity criterion accepted in conventional in vitro cytotoxic screening tests. Two compounds revealed weak cytotoxic activity with ID50 higher than 4 microg/ml and five compounds were inactive.

Antineoplastic Agents↗
PubMed2006

[Cloning and sequencing of the GTP cyclohydrolase I function region of azole target enzyme gene in artificially induced resistant Candida albicans].

OBJECTIVE: To study the relationship between gene mutation of GTP cyclohydrolase I function region in lanosterine 14 alpha-demethylase (14-DM) DNA sequence and drug resistance of Candida albicans. METHODS: One standard strain and 2 isolate strains of Candida albicans were induced artificially by fluconazole plus albendazole. The gene fragments of the 3 strains and another 2 clinical isolates which were resistant to fluconazol were detected by PCR, and then cloned onto pMD-18T vectors to sequence and analyze the change of gene sequence after the induction. RESULTS: The sequences underwent substantial gene mutations after induction. Some of the mutations resulted in alteration of amino acids. The sequence change and subsequent alteration of amino acids in the tested strains coincided with those in the clinical isolates. CONCLUSION: Gene mutation and alteration of amino acid of 14-DM GTP domain are related to azole-resistance in Candida albicans.

Albendazole↗
PubMed2004

[The effect of fluorine substituent on radiochemical stability of some steroid and azole derivatives].

Radiochemical stability of three fluorine containing therapeutic substances: dexamethasone, fludrocortisone acetate (steroid derivatives) and fluconazole (azole derivative) has been studied. The compounds in the solid phase were exposed to ionising radiation in the form of electron beam using doses of 20-400 kGy. The inital and irradiated compounds were subjected to comparative analyses by organoleptic, spectrophotometric (UV and IR) and chromatographic (TLC and HPLC) methods. For all compounds studied the irradiation was found to lead to a decrease in the active substance content (HPLC), appearance of radiolysis products (TLC), changes in the physical and chemical properties such as colour (fluconazole), formation of agglomerates (dexamethasone), decrease (dexamethasone, fludrocortisone acetate) or increase in UV absorption (fluconazole). The two steroid derivatives were found resistant to ionising radiation at doses of 25-50 kGy and can be sterilised by radiation, whereas fluconazole was too sensitive to electron beam irradiation and should be sterilised by other methods. The results were compared with those of earlier studies on radiation sterilisation of other steroid derivatives. An interesting conclusion is that the presence of the fluorine atom in the molecule of fludrocortisone acetate has no significant effect on its radiochemical stability when compared with that of hydrocortisone acetate--the analogue without fluorine.

Dexamethasone↗
PubMed1990

Studies on antifungal agents. Novel cis-5-alkyl (or alkenyl)-3-phenyl-3-(1H-azol-1-ylmethyl)-2-methyl-isoxazolidine derivatives.

The preparation and in vitro antifungal activity of a novel series of cis-5-alkyl (or alkenyl)-3-phenyl-3-(1H-azol-1-ylmethyl)-2-methylisoxazol idines are described. The overall activity of the 3-(1H-imidazol-1-ylmethyl) analogues was higher than that of the corresponding 3-(1H-1,2,4-triazol-1-ylmethyl) derivatives. Compound 4b emerged as the most potent derivative. When compared to ketoconazole, several of the analogues tested demonstrated equipotent or superior activity against Trichophyton and Candida sp.

Antifungal Agents↗
PubMed1989

5-Lipoxygenase inhibition by antifungal azole derivatives: new tools for immunosuppression?

The effect of novel azole derivatives (itraconazole and fluconazole) on 5-lipoxygenase activity was examined using human polymorphonuclear leukocytes (PMNL) as the enzyme source. The novel imidazole derivative itraconazole proved to be a potent inhibitor (IC50 2 X 10(-6) M) of 5-lipoxygenase activity. In contrast, fluconazole, an antifungal agent with bistriazole structure, had no effect on the Ca2+ ionophore A 23187-induced formation of 5-lipoxygenase metabolites in PMNL.

Antifungal Agents↗
PubMed1986

Azole antifungal drugs in treatment of coccidioidomycosis.

For two decades amphotericin B has been the only antifungal drug with proven efficacy against Coccidioides immitis. The introduction of miconazole in the late 1970s ushered in a new era of antifungal therapy. Miconazole induced remissions in patients with disease refractory to amphotericin B and in patients who had relapsed after amphotericin B treatment. Almost as important, miconazole did not have the nephrotoxicity associated with amphotericin B. However, the necessity of intravenous administration and other toxicities limited the value of miconazole. The first child of miconazole was ketoconazole, which could be administered orally and had markedly less toxicity than amphotericin B or miconazole. Because coccidioidomycosis challenges any antifungal drug, doses were increased to as much as 2,000 mg/d. Ketoconazole can be used for long terms and at high doses, with many patients brought into remission. However relapses and failures still occurred; dose-related endocrine and gastrointestinal toxicities were uncovered. A third generation of azoles, the triazoles, was introduced to minimize these adverse effects, yet retain the efficacy of ketoconazole. Early clinical trials are promising for itraconazole. Other triazoles with advantageous pharmacokinetic properties are also coming into clinical trials. Shortly, we are likely to have available a whole range of antifungal agents for treatment of this most frustrating disease.

Antifungal Agents↗
PubMed2002

Mechanism of azole antifungal activity as determined by liquid chromatographic/mass spectrometric monitoring of ergosterol biosynthesis.

A liquid chromatography/mass spectrometry (LC/MS) method for separation and characterization of ergosterol biosynthetic precursors was developed to study the effect of Posaconazole on sterol biosynthesis in fungi. Ergosterol biosynthetic precursors were characterized from their electron ionization mass spectra acquired by a normal-phase chromatography, particle beam LC/MS method. Fragment ions resulting from cleavage across the D-ring and an abundant M - 15 fragment ion were diagnostic for methyl substitution at C-4 and C-14. Comparison of the sterol profile in control and treated Candida albicans incubations showed depletion of ergosterol and accumulation of C-4 and C-14 methyl-substituted sterols following treatment with Posaconazole. These C-4 and C-14 methyl sterols are known to be incapable of sustaining cell growth. The results demonstrate that Posaconazole exerts its antifungal activity by inhibition of ergosterol biosynthesis. Furthermore, Posaconazole appears to disrupt ergosterol biosynthesis by inhibition of lanosterol 14alpha-demethylase.

Antifungal Agents↗
PubMed2000

The use of the substrate-heme complex approach in the design, synthesis, biochemical evaluation, and rationalization of the inhibitory activity of a range of azole compounds against cholesterol side chain cleavage enzyme.

Here, we report the synthesis and biochemical evaluation of a number of compounds as potent inhibitors of cytochrome P450 enzymes, such as aromatase (AR), but not cholesterol side chain cleavage (CSCC). This is a crucial enzyme in the steroidal cascade and its inhibition results in major side-effects, as a result, the ability of compounds to specifically inhibit enzymes such as AR but not CSCC would be an important factor in the drug design process.

Animals↗
PubMed1997

Antifungal, antibacterial, antiviral and cytotoxic activity of novel thio- and seleno-azoles.

A series of pentaatomic heterocyclic compounds containing sulphur or selenium in position 2, were tested for cytotoxicity, antiviral and antimicrobial activities. Generally, selenium-containing compounds were more toxic than the corresponding sulphur-containing ones (30-75 times more toxic) and, furthermore, the biological activity against some microorganisms was also enhanced. In particular, some selenium-containing derivatives exerted an inhibitory activity on plant pathogenic fungi at doses markedly lower than the toxic ones, showing an interesting selectivity of action. In this case the tested compounds appeared more active than ketoconazole, the control used, with an almost comparable degree of cytotoxicity.

Animals↗
PubMedDate not supplied

Quantitative polyphosphate-induced "prebiotic" peptide formation in H2O by addition of certain azoles and ions.

Aqueous solutions of 0.1 M amino acid and 0.1 M trimetaphosphate maintained at chosen pH values between 8.0 and 10.5 and at room temperature in the presence of imidazole or 1,2,4-triazole give rise after a few days to the corresponding peptides. Yields are highest when the pH is adjusted with concentrated NaOH or KOH instead of ammonia; in some cases glycine is quantitatively transformed within 10-15 days into peptides, mainly di-and tripeptides.

Azoles↗
PubMedDate not supplied

Azole antifungals.

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Antifungal Agents↗