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PubMedDate not supplied

Susceptibility of clinical isolates of Candida spp. to terconazole and other azole antifungal agents.

Terconazole is a triazole ketal derivative with potent, broad-spectrum antifungal activity. We investigated the in vitro activity of terconazole, miconazole, and clotrimazole, against 94 clinical isolates of Candida spp.: C. albicans (n = 68), C. tropicalis (n = 18), and C. parapsilosis (n = 8). In vitro susceptibility testing was performed using a broth microdilution method. The minimal inhibitory concentrations of terconazole were less than those of miconazole against C. albicans and C. parapsilosis but higher against C. tropicalis. Terconazole was more active than clotrimazole against C. parapsilosis and less active against C. albicans and C. tropicalis. Terconazole inhibited the uptake of 14C-labeled glucose, leucine, and hypoxanthine into C. albicans and caused the rapid release of intracellular K+. Based on these studies, terconazole has promising anticandidal activity and warrants further in vitro and in vivo investigation.

Antifungal Agents↗
PubMed2005

Pyrrolo[1,2-a][1,4]benzodiazepine: a novel class of non-azole anti-dermatophyte anti-fungal agents.

Broad screening revealed compound 1a to be a novel anti-fungal agent with high specificity towards dermatophytes. The anti-fungal structure-activity relationship of this novel class of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines is described together with its mode of action that appeared to be the inhibition of squalene epoxidase. Preliminary in vivo results of the most active compounds are also reported.

Antifungal Agents↗
PubMed2006

In vitro interactions of anidulafungin with azole antifungals, amphotericin B and 5-fluorocytosine against Candida species.

Anidulafungin, an echinocandin, is in late stage development for the treatment of fungal infections. We investigated the activity of anidulafungin in combination with other antifungal agents (fluconazole, itraconazole, ketoconazole, amphotericin B and 5-fluorocytosine) against four isolates each of Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis, and two isolates of Candida krusei using a macrobroth chequerboard method with interactions evaluated by fractional inhibitory concentration indices (FICIs). Additive activity (FICI > 0.5 to 1) or indifference (FICI > 1 to < 4) was observed in 85 of 90 interactions of anidulafungin with another antifungal agent. Synergy with itraconazole (FICI or=4), a drug rarely used systemically, was noted for four strains of C. tropicalis. The combination of anidulafungin and amphotericin B demonstrated additive activity for each of the 18 isolates of Candida tested. These results suggest additional studies are warranted, for example in animal models, to evaluate further the potential of combination antifungal therapy with anidulafungin for Candida infections.

Amphotericin B↗
PubMed1999

Synthesis and biological evaluation of [alpha-(1,5-disubstituted 1H-pyrazol-4-yl)benzyl]azoles, analogues of bifonazole.

A series of pyrazole analogues of bifonazole, an antifungal drug used in clinical practice, 2a-h and 4a-h were synthesized and tested in vitro against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, with no significant results. Imidazoles 2a-h were also tested in vivo for antiarrhythmic and antihypertensive activities; two of these compounds showed moderate activity against ventricular fibrillation caused by aconitine in rats. The above compounds were prepared by reaction of phenyl-[5 substituted 1-phenyl (or 1-methyl)-1H-pyrazol-4-yl]methanols with N,N'-carbonyldiimidazole (2a-h) or of the respective chloro derivatives with 1H-1,2,4-triazole (4a-h).

Animals↗
PubMed1998

Should resistance to azole antifungals in vitro be interpreted as predicting clinical non-response?

Published data relating clinical treatment outcomes to susceptibility of Candida species in vitro for the triazole antifungal agents fluconazole and itraconazole show a clear association between rates of treatment failure and rising minimal inhibitory concentrations for the infecting fungal isolate. However, more than 50% of patients infected with an isolate 'resistant' to a triazole by NCCLS breakpoint criteria respond successfully to treatment with the triazole. Data for antibacterial agents similarly show that the association between resistance in vitro and treatment failure in vivo is far less than perfect. Susceptibility testing therefore falls into a category similar to that of weather forecasting. Despite good test standardization and sophisticated technology, the forecasts successfully predict trends, but cannot accurately foresee temperatures or levels of precipitation at a specific time in a specific location.

Journal Article↗
PubMed2005

Energetic azolium azolate salts.

Energetic salts comprising substituted imidazolium and 1,2,4-triazolium cations and 4,5-dinitro-imidazolate and 5-nitrotetrazolate anions were synthesized and characterized. On the basis of experimentally obtained heats of combustion, the calculated heats of formation range from deltaHf(o) degrees = 80 (3) to 1071 kJ/mol (13). Imidazolate salts are more dense but have lower heats of formation than their tetrazolate analogues. Salts 4, 5, 8, and 11-14 fall into the ionic liquid class (mp < 100 degrees C). The structure of 1,2,4-triazolium 5-nitrotetrazolate (10) was confirmed by X-ray analysis.

Journal Article↗
PubMed1999

Syntheses and Structures of Bis(azole)difluorosulfuranes.

Bis(imidazole)sulfur difluoride (4), bis(pyrazole)sulfur difluoride (6), and bis(1,2,4-triazole)sulfur difluoride (8) are formed in the reactions of N-(trimethylsilyl)imidazole, N-(trimethylsilyl)pyrazole, and 1-(trimethylsilyl)-1,2,4-triazole with SF(4), in high yield. The ring systems in these three molecules occupy equatorial positions in the pseudo-trigonal-bipyramidal coordination sphere of the central sulfur atoms. The angles between the planes of the ring substituents and the FSF axis for 4 and 6 are in the range 23.6-35.3 degrees, and in 8 the triazole rings are almost parallel (deviation 1.7 degrees ). The interaction between the heterocyclic substituents and the sulfur centers and their influence on the axial and equatorial bonds is discussed.

Journal Article↗
PubMed2002

A novel isomerization on interaction of antitumor-active azole-bridged dinuclear platinum(II) complexes with 9-ethylguanine. Platinum(II) atom migration from N2 to N3 on 1,2,3-triazole.

The reactions of the dinuclear platinum(II) complexes, [[cis-Pt(NH(3))(2)](2)(mu-OH)(mu-pz)](NO(3))(2) (1, pz = pyrazolate), [[cis-Pt(NH(3))(2)](2)(mu-OH)(mu-1,2,3-ta-N1,N2)](NO(3))(2) (2, 1,2,3-ta = 1,2,3-triazolate), and a newly prepared [[cis-Pt(NH(3))(2)](2)(mu-OH)(mu-4-phe-1,2,3-ta-N1,N2)](NO(3))(2) (3, 4-phe-1,2,3-ta = 4-phenyl-1,2,3-triazolate), whose crystal structure was determined, with 9-ethylguanine (9EtG) have been monitored in aqueous solution at 310 K by means of (1)H NMR spectroscopy. The dinuclear platinum(II) complexes 1-3 each react with 9EtG in a bifunctional way to form 1:2 complexes, [[cis-Pt(NH(3))(2)(9EtG-N7)](2)(mu-pz)](3+) (4), [[cis-Pt(NH(3))(2)(9EtG-N7)](2)(mu-1,2,3-ta-N1,N3)](3+) (5), and [[cis-Pt(NH(3))(2)(9EtG-N7)](2)(mu-4-phe-1,2,3-ta-N1,N3)](3+) (6). The reactions of 2 and 3 involve a novel isomerization, in which the Pt atom, initially bound to N2 on the 1,2,3-ta, migrates to N3 after the first substitution by N7 of 9EtG. This isomerization reaction has been unambiguously characterized by 1D and 2D NMR spectroscopy and pH titration. The reactions of 2 and 3 with 9EtG show faster kinetics, and the second-order rate constants (k) for the reactions of 1-3are 1.57 x 10(-4), 2.53 x 10(-4), and 2.56 x 10(-4) M(-1) s(-1), respectively. The pK(a) values at the N1H site of 9EtG were determined for 4-6 from the pH titration curves. Cytotoxicity assays of 1-3 were performed in L1210 murine leukemia cell lines, respectively sensitive and resistant to cisplatin. In the parent cell line, 2 and 3 exhibit higher cytotoxicity compared to cisplatin, especially, 2 is 10 times as active as cisplatin. 1 was found to be less cytotoxic than cisplatin, but still in the active range and more active than cisplatin in a cisplatin-resistant cell line.

Animals↗
PubMed2005

Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates.

Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.

Catalysis↗
PubMed1984

Synthesis and evaluation of furan, thiophene, and azole bis[(carbamoyloxy)methyl] derivatives as potential antineoplastic agents.

A series of bis(hydroxymethyl)-substituted heterocycles were synthesized and converted to the corresponding bis(methylcarbamate) derivatives. The heterocyclic systems studied were based on 2-phenyl-3-methylfuran (2-4), 1-phenylpyrazole (5-7), 1-phenyl-5-methylpyrazole (9-11), 1-phenyl-5-methylthiophene (13), 1-phenyl-1,2,3-triazole (14), 3-phenylisoxazole (15), 3-phenylisothiazole (16), 2-phenylthiazole (17), and 2-phenyloxazole (18). None of the bis(carbamates) prepared was active against murine P388 lymphocytic leukemia. Pyrrole bis(carbamates) 20 and 21, which exhibited antileukemic activity, also showed reactivity toward 4-(p-nitrobenzyl)pyridine while the inactive bis(carbamates) were unreactive in the 4-(p-nitrobenzyl)pyridine assay.

Animals↗
PubMed1996

Diheteroarylmethanes. 5.(1) E-Z Isomerism of Carbanions Substituted by 1,3-Azoles: (13)C and (15)N pi-Charge/Shift Relationships as Source for Mapping Charge and Ranking the Electron-Withdrawing Power of Heterocycles.

Previously proposed pi-charge/shift relationships have been applied to (13)C and (15)N shifts of the carbanions of 2-benzylazoles (thiazole, oxazole, and imidazole), their corresponding benzo-fused analogs, and bis(2-azolyl)methanes (azolyl groups as above). In this way it is possible to rank the pi electron-withdrawing power of these heterocycles in terms of charge demands c(X), a quantity representing the fraction of pi negative charge withdrawn (delocalized) by the ring. The results indicate that c(thiaz) > c(oxaz) > c(imidaz); furthermore, benzoazoles are more efficient than monocyclic systems in delocalizing the negative charge. The charge demand c(X) of imidazole is the smallest among the heteroaromatics so far considered, being even smaller than that of the phenyl ring. As a consequence, the negative charge in the anion of 2-benzyl-N-methylimidazole is predominantly transferred from the carbanionic carbon to the phenyl group rather than to the imidazolyl residue. The high double bond character of the bond linking the carbanionic and ipso phenyl ring carbons leads to room temperature (13)C shift anisochrony of the meta and meta' and ortho and ortho' positions of the phenyl ring. In all of the other cases, hindered rotation is observed at room temperature between the carbanionic carbon and position 2 of the heterocycle. A single set of resonances is presented by the bis(heteroaryl)methyl carbanions. pi-Charge/shift relationships allow for the accurate pi-charge mapping in these carbanionic systems, and the results point to considerable delocalization of the electron pair(s) of the oxygen and pyrrolic nitrogen atoms at position 1 in oxazole and imidazole toward the pyridic nitrogen at position 3 of the rings (in both the neutrals and the carbanionic species). On the contrary, not only does the sulfur atom in thiazole derivatives not delocalize any negative charge in the anions but it is barely involved in any pi-donation to the pyridic nitrogen atom at position 3 also in the neutrals.

Journal Article↗
PubMed2006

Binding of novel azole-bridged dinuclear platinum(II) anticancer drugs to DNA: insights from hybrid QM/MM molecular dynamics simulations.

Dinuclear Pt-containing compounds might be used to overcome the intrinsic and acquired cell resistance of widely used anticancer drugs such as cisplatin. Recently, the complexes [[cis-Pt(NH3)2]2(mu-OH)(mu-pz)](NO3)2 (with pz = pyrazolate) (1), [[cis-Pt(NH3)2]2(mu-OH)(mu-1,2,3-ta-N(1),N(2))](NO3)2 (with ta = 1,2,3-triazolate) (2), and the binding of 1 to d(CpTpCpTpG*pG*pTpCpTpCp) have been characterized. Here we provide the structural and electronic properties of the free drugs, of the intermediates of binding to guanine bases, and of the products, by performing DFT calculations. Our results show that in 2 an isomerization of the Pt-coordination sphere from N(2) to N(3) of the triazolate unit determines a thermodynamic stabilization of approximately 20 kcal/mol as a consequence of the formation of an allylic structure. In addition, hybrid quantum-classical molecular dynamics simulations of 1 and 2 DNA adducts have shed light on the structural distortions that the drugs induce to the DNA duplex. Our calculations show that the rise and the tilt of the two adjacent guanines are identical in the presence of 1 and 2, but they markedly increase when 2 binds in the N(1),N(3) fashion. In addition, the drugs do not provoke any kink upon binding to the double-stranded DNA, suggesting that they may act with a mechanism different than that of cisplatin. The accuracy of our calculations is established by a comparison with the NMR data for the corresponding complex with 1.

Algorithms↗