Fluconazole, synthesis

The Corey-Chaykovsky reaction incited some applications in medicinal chemistry. During the synthesis of analogs of fluconazole, an azole antifungal agent, treatment of 49 with 1 led to the corresponding epoxide, which was subsequently... 

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) ... 

The answer is a. (Hardman, p 1180. Katzung, pp 817—819J Fluconazole indirectly inhibits ergosterol synthesis. It inhibits cytochrome P4.50, which is a key enzyme system for cytochrome P4.5O-dependent sterol 14-a-demethylase. This leads to accumulation of 14-a-sterols, resulting in impairment of the cytoplasmic membrane. 

Fluconazole and itraconazole are newer, orally effective triazole derivatives. The topically active allylamine naftidine and the morpholine amorolfine also inhibit ergosterol synthesis, albeit at another step. 

Mechanism of Action. Fluconazole and similar agents (itraconazole, ketoconazole) inhibit certain enzymes in fungal cells that are responsible for the synthesis of important sterols.9,15 A deficiency of these... 

Mechanism of Action. Itraconazole works like fluconazole and similar azoles. These drugs disrupt membrane function of the fungal cell by inhibiting the synthesis of key membrane components such as sterols, and by directly damaging other membrane components such as phospholipids. Impaired membrane function leads to metabolic abnormalities and subsequent death of the fungal cell. 

Mechanism of Action. Voriconazole inhibits sterol biosynthesis in fungal cell membranes.53 That is, this drug acts like fluconazole and similar agents to impair membrane synthesis, which results in membrane integrity loss and death of the fungal cell. 

The synthesis follows the analysis exactly giving fluconazole 60 in only 5 steps from available starting materials. This synthesis should demonstrate that important modem drugs are made by the style of reactions that you are meeting in this book.6... 

Amphotericin B preferentially damages ergosterol-containing membranes fluconazole and several congeners are inhibitors of ergosterol synthesis. 

Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity, see below) it is widely distributed in tissues but concentrations in CSF and urine are low its action is terminated by metabolism by cytochrome P450 3A (CYP 3A) (t) 8 h). Ketoconazole is effective by mouth for systemic mycoses (see Table 14.2) but has been superseded by fluconazole and itraconazole for many indications largely on groimds of improved pharmacokinetics, imwanted effect profile and efficacy. Impairment of steroid synthesis by ketoconazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer. 

The azoles (ketoconazole, fluconazole, clotrimazole, miconazole, and itraconazole) kill fungi by interfering with ergosterol synthesis. The mechanisms of action, clinical uses, biodisposition, and side effects are considered. 

Fluconazole Imidazole antifungal inhibits ergosterol synthesis. Used in esophageal and... 

Selective alkylation of 1,2,4-triazole in position 1 is of primary interest for the synthesis of biologically active molecules such as fungicides (fluconazole, flutriafole,... 

---