Fluconazole structure

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Fluconazole was shown to be crystallizable in the form of a monohydrate and as a 1/4 ethyl acetate solvate, as well as a new nonsolvated form [56], In the hydrate phase the water molecules were established as isolated sites, while the ethyl acetate molecules occupied constricted channels in its phase. In all of the structures, the fluconazole molecule adopted a common overall conformation, but one that was capable of some degree of flexibility. Hydrogen-bonding effects were deduced to be dominant in determining the structure of the different solvatomorphs. 

In keeping with the simplicity of its structure, fluconazole can be synthesized in two steps from commercially available starting materials (Scheme 5.3). Metallation of 1-bromo-2,4-difluorobenzene with butyllithium in ether gave the corresponding aryllithium. 

Posaconazole is similar in structure to itraconazole. It was well tolerated and as effective as fluconazole 100 mg in two large randomized comparisons in HIV-infected patients with oropharyngeal candidiasis. In a salvage study in patients with a variety of invasive fungal infections, there were response rates of 44-80% in patients with aspergillosis, fusariosis, cryptococcosis, candidiasis, and pheohyphomycoses after 4-8 weeks of therapy (1,2). 

Ravuconazole is similar in structure to fluconazole. It has a long half-life suitable for once-daily dosing. 

Voriconazole is a triazole that is structurally related to fluconazole. It has two interesting properties, activity against Aspergillus species and sufficient solubility in... 

Fig. 4.3 Structures of polyene (amphotericin B) and azole (itraconazole, fluconazole, miconazole and ketoconazole) antifungal agents.

Thompson, C.M. et al., A comparison of accurate mass techniques for the structural elucidation of fluconazole, Rapid Commun. Mass Spectrom., 17(24), 2804, 2003. 

Ravuconazole - structurally similar to fluconazole and voriconazole and active against Candida species, Aspergillus species and C. neoformans. 

Voriconazole (Vfend UK-109,495) is a triazole with a structure similar to fluconazole but has increased activity in vitro, an expanded spectrum, and poor aqueous solubility (pregnancy risk category C). 

Seward HE, Roujeinikova A, McLean KJ, Munro AW, Leys D (2006) Crystal structure of the Mycobacterium tuberculosis P450 CYP121-fluconazole complex reveals new azole drug-P450 binding mode. J Biol Chem 281 39437-39443... 

Figure 1. (a) Chemical structure of the host p-cyclodextrin (p-CD) (b) truncated cone shape of p-CD and (c) guest fluconazole (FLZ). 

Here we present a study highlighting the interaction between antifungal drug fluconazole and P-cyclodextrin, using NMR as a spectroscopic tool. In order to better understand the structure of the inclusion complex between the two chemical species, we have complemented these studies with molecular modeling simulations. 

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