Azole derivative

TABLE r-28, MEAN POSITIONS OF THE C-H VIBRATIONS OF TH AZOLE DERIVATIVES... 

Because of their limited, activity, small spectmm, and side effects, the older topical antimycotics have generally been surpassed by newer antimycotic chemotherapeutic agents. These newer antimycotics for topical use iaclude the imida2ole derivatives clotrimazole, miconazole, econazole, isoconazole, sulconazole, fenticonazole, oxiconazole, bifonazole, butoconazole, ziaoconazole, tioconazole, and the triazole derivative, terconazole (Table 2) (5—7). The iatroduction of the azole derivatives represents a milestone ia the treatment of mycoses. 

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

Azolinone derivatives and the corresponding thiones and imines are listed in Table 18 only substituted derivatives have been measured frequently. The chemical shifts of non-aromatic azole derivatives are given in Tables 19-21 relatively few data are available and these are generally for substituted derivatives rather than for the parent compounds. 

Electrophilic mercuration of isoxazoles parallels that of pyridine and other azole derivatives. The reaction of 3,5-disubstituted isoxazoles with raercury(II) acetate results in a very high yield of 4-acetoxymercury derivatives which can be converted into 4-broraoisoxazoles. Thus, the reaction of 5-phenylisoxazole (64) with mercury(II) acetate gave mercuriacetate (88) (in 90% yield), which after treatment with potassium bromide and bromine gave 4-bromo-5-phenylisoxazole (89) in 65% yield. The unsubstituted isoxazole, however, is oxidized under the same reaction conditions, giving mercury(I) salts. 

Metalation of 4,5-dihydro-2-[(7 )-sulfinylmethyl]oxazoles (e.g., 2) with butyllithium at -90 C and reaction of the chiral azaenolates with aldehydes furnishes the hydroxyalkylated sulfinylox-azole derivatives 3 which are desulfurized to give the 4,5-dihydro-2-(2-hydroxyalkyl)oxazoles 4. The corresponding 3-hydroxy acids 5 are obtained by acidic hydrolysis in 60-85% overall yield and 26-53% ee31. 

Benzotriazole can exist in two tautomeric forms, l-//-benzotriazole (6.46, R = H) and 2-/f-benzotriazole. If the aromatic ring contains a substituent, the 1- and 3-nitrogen atoms of the triazole are not equivalent, and therefore a 3-//-benzotri-azole derivative can also exist. The equilibrium between the 1 -H and 2-H tautomers of benzotriazoles is strongly on the side of the 1 -H tautomer, in contrast to triazole where the 2-H tautomer is dominant. Tomas et al. (1989) compared experimental data (enthalpies of solution, vaporization, sublimation, and solvation in water, methanol, and dimethylsulfoxide) with the results of ab initio theoretical calculations at the 6-31G level. 

This condition is probably fulfilled for [29a-29e], [29/], and for the N-methylimid-azole derivative [29f] as well, because all these molecules have only CH bonds pointing to their periphery. 

Lewis, D. F. V., Wiseman, A., and Tarbit, M. H. (1999) Molecular modeling of lanosterol 14-alpha-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives../. Enz. Inhib. 14, 175-192. 

The azole derivatives for systemic administration include the imidazoles ketoconazole and miconazole and the triazoles fluconazole, itraconazole, posaconazole and voriconazole. They are broad spectrum antifungals and have activity against several dermatophytes, Candida, Cryptococcus and other fungi that cause deep-seated infections. 

Topical azole derivatives include the imidazoles bifonazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, lanoconazole, flutrima-zole and sertaconazole. These drugs show activity against the dermatophytes Epidermophyton, Mi-crosporum and Trichophyton. They are also effective against the yeasts Candida albicans and Pityrospo-rum orbiculare. Local side effects include pruritus, erythema and local irritation. Allergic dermatitis is rare. 

When using azole derivatives the experimental determination of lone-pair ionization potentials by photoelectron spectroscopy suffers from considerable band overlap involving the ionization of the 7r-system (69MI1 74PMH1 79JOC2093 80JHC689). 

Oral Antifungal Agents ORAL AZOLE DERIVATIVES... 

Azole derivatives currently available for oral treatment of systemic mycosis include fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and others. As discussed in Chapter 48, imidazole derivatives act by affecting the permeability of the cell membrane of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell. 

F.C. Odds, Resistance of yeasts to azole-derivative antifungals, /. Antimicrob. Chemother., 31, 463, 1993. 

Inasmuch as both types of tri azole derivs(when contg one or two alkyls of low mw) are high-... 

Keywords 4-bromophenacyl bromide, azole derivative, /V-alkylation, microwave irradiation, azalieterocycle... 

Adhikari S, Sprinz H, Brede 0 (2001) Thiyl radical induced isomerization of unsaturated fatty acids determination of equilibrium constants. Res Chem Intermed 27 549-559 Adhikary A, Bothe E, Jain V, von Sonntag C (2000) Pulse radiolysis of the DNA-binding bisbenzimid-azole derivatives Hoechst 33258 and 33342 in aqueous solution. Int J Radiat Biol 76 1157-1166 Akhlaq MS, von Sonntag C (1986) Free-radical-induced elimination of H2S from dithiothreitol. A chain reaction. J Am Chem Soc 108 3542-3544... 

A simple calculation can serve to demonstrate this chemical variability (Figure 14). If one designates the substituents of the N-substituted azoles as X, Y, Z and the number of variations as n, then the total number N of azole derivatives possible can easily be calculated. If n = 200, which is certainly a very modest number of different X, Y, Z substituents, then this means that with imidazole and triazole as components, it is possible to make 5.4 million different compounds ... 

One of the special features of azole compounds is the abundance of synthetic possibilities and therefore the abundant selection opportunities for biology and medicine. By examination of the properties of azole derivatives, one can recognize other applications for them apart from the control of fungi pathogenic to plants and man. Some of the azole derivatives, such as lombazole, exhibit... 

To date, this worldwide activity has led to a whole series of highly active azole derivatives developed for practical use in medicine and agriculture (Figure 15). 

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