Azoles

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Azole antifungal agents include imidazole and triazole derivatives that prevent the synthesis of ergosterol, a major component of fungal membranes, by inhibiting the cytochrome P-450-dependent enzyme 14a-lanosterol demethylase (CYP51) [10,11]. This enzyme contains an iron protoporphyrin unit located in its active site, which catalyzes the oxidative removal of the 14a-methyl group of lanosterol, by typical monooxygenase activity [12]. Azoles bind to the iron of the porphyrin [13] and cause the blockage of the fungal ergosterol biosynthesis pathway by blocking access of lanosterol to the active site of the enzyme. The depletion of ergosterol and the concomitant accumulation of 14a-methylated sterols alter the fluidity of the fungal membrane causing a reduction in the activity of membrane-associated enzymes and increased permeability. The net effect of these changes is to inhibit fungal growth and replication [14].

Imidazole derivatives, such as bifonazole, clotrimazole, econazole and micon-azole were the first group of azole antifungal agents used in clinical practice in the 1970s. Recently, 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives (such as compound 1) related to bifonazole were reported, which showed potent antifungal activities both in vitro and in vivo experiments against Candida albicans and other Candida species. Interestingly, some derivatives were proven active in vitro against fluconazole resistant strains, with MIC50 ranging from 0.016 to 0.25 mg/ml [15-18]. Ketoconazole (2), a phenethylimidazole characterized by a dioxolane ring, was the first agent endowed with a wide spectrum of activity against both a variety of yeasts and dimorphic fungi. Further, 2 showed good bioavail-ability after oral administration and was used against serious invasive fungal infections. The clinical use of ketoconazole has been related to some adverse effects in healthy adults, especially local reactions, such as severe irritation, pruritus and stinging. Dispersions of ketoconazole in aqueous lipid nanoparticles were assessed as useful for targeting this drug into topical routes, minimizing the adverse side effects and providing a controlled release [19]. Ketoconazole has been given a teratogenic classification of C by the US Food and Drug Administration (FDA), thus leading research to be directed toward 1,2,4-triazole derivatives.

Itraconazole (3) is a triazole derivative related to 2, which showed a broader spectrum of activity if compared to that of the parent compound. A recent study reported three itraconazole metabolites, hydroxy-itraconazole, keto-itraconazole and N-desalkyl-itraconazole that were competitive inhibitors of CYP3A4 [20]. A great enhancement of bioavailability of 3 after initial dosing, not influenced by fed/ fasted state, was obtained with a self-emulsifying drug-delivery system composed of TranscutolĀ®, PluronicĀ®, L64 and tocopherol acetate [21].

Posaconazole (4) is a second-generation triazole antifungal agent that is structurally related to itraconazole. The antifungal spectrum of posaconazole is broad and includes causative agents of invasive fungal infections such as Candida species, Aspergillus species, non-Aspergillus hyalohyphomycetes, phaeohyphomycetes, zygo-mycetes and endemic fungi. Posaconazole is presently involved in phase III trials. It is effective in vitro and in vivo against several fungi that are resistant to standard antifungals. It is the most active triazole against filamentous fungi, inhibiting 95% of isolates at concentrations of 1 mg/ml or below [22-25]. In a double-blinded,

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multicenter clinical trial for prophylaxis of invasive fungal infections, posaconazole was compared with fluconazole in 600 patients who had undergone hematopoietic stem cell transplant (HSCT) with graft-versus-host disease. Posaconazole (200 mg every 8 h) was significantly superior to fluconazole (400 mg once a day) in preventing aspergillosis [26]. Posaconazole demonstrated in vitro and in vivo activity against zygomycetes in two open-label, non-randomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections. It was given as an oral suspension of 200 mg four times a day or 400 mg twice a day. Overall, 19 of 24 subjects (79%) survived infection [27]. Posaconazole 5, 25 or 100mg/kg as an oral suspension was effective in prolonging survival of mice in a murine model of central nervous system (CNS) aspergillosis [28]. A clinical trial was conducted to evaluate the safety and efficacy of posaconazole in subjects with invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy. Subjects received posaconazole oral suspension 800mg/day in divided doses for up to 1 year. Successful outcomes were observed in 48% subjects with cryptococcal meningitis, and 50% of subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated, thus suggesting that as an oral medication it could provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents [29].

R126638 (5) was developed as a novel azole agent related to posaconazole, which showed very high levels of in vitro antifungal activity. Its potency was confirmed in in vivo models of cutaneous infections caused by Microsporum canis, and Thricophy-ton mentagrophytes in guinea pigs and mice. The ED50 of R126638 was calculated to be <0.63mg/kg, superior to that of itraconazole used as a reference drug, which showed ED50 = 3.02mg/kg [30,31].

Fluconazole (DiflucanĀ®) (6) is a triazole derivative that shows both oral and parenteral fungistatic activity. Extensive clinical studies have demonstrated remarkable efficacy, favorable pharmacokinetics and a reassuring safety profile for 6, all of which have contributed to its widespread use [32]. The efficacy, tol-erability and safety of oral fluconazole given at 300 mg once weekly for 2 weeks was demonstrated for the treatment of Tinea versicolor [33]. Pulse fluconazole therapy, 300 mg once weekly, is effective against foot nail infections [34]. The upregulation of the ATP binding cassette (ABC) transporter-encoding gene AFR1 in C. neoformans was shown in vivo in a mouse model of systemic cryptococcosis treated with 6. The reported findings indicate that the upregulation of the AFR1 gene is an important factor in determining the in vivo resistance to fluconazole [35]. Fosfluconazole, the phosphate prodrug of fluconazole, was developed as highly soluble form compared with the parent drug. It could be useful against fungal peritonitis in continuous ambulatory peritoneal dialysis patients given its high water solubility. After intravenous bolus injection of fosfluconazole 50-2000 mg, a rapid convertion to fluconazole was observed. It had a volume of distribution at the higher doses similar to the extracellular volume in man (0.2l/kg) and was eliminated with a terminal half-life of 1.5-2.5 h [36,37].

The major drawbacks of fluconazole were its poor bioavailability and the delayed development of an intravenous preparation. A second-generation of triazole antifungal agents was recently developed to address these limitations, including voriconazole (7), ravuconazole (8) and posaconazole (4). These new agents appeared to have expanded antifungal activity compared to prior azoles [38-40].

Voriconazole (7) is a synthetic derivative of fluconazole that was approved by FDA in 2002. Replacement of one of the triazole rings of 6 with a fluorinated pyrimidine and the addition of an a-methyl group resulted in expanded activity, compared with that of fluconazole. Voriconazole is broadly active against

many species of Aspergillus, including A. terreus, and against all Candida species, including C. krusei, C. glabrata and strains of C. albicans resistant to fluconazole [41-43]. It is available in both intravenous (vials containing 20 mg), and oral formulation (50 and 200mg film-coated tablets) [41]. Voriconazole at 0.125-0.5mg/l, but not itraconazole and other azoles, inhibited conidiation in A. fumigatus, A. flavus, A. niger and A. nidulans. The authors suggest a mechanism unrelated to the inhibition of 14a-methyl lanosterol demethylase, perhaps directed against the formation of the conidia [44]. A comparison of the fungicidal activity against A. fumigatus hyphae, emphasized the higher potency of voriconazole versus amphotericin B. Approximately 99% killing of hyphae grown in peptone yeast extract glucose broth was obtained for voriconazole at 1 mg/l after 48 h of exposure, whereas amphotericin B at the same concentration yielded 82% killing after at the same time [45]. Topical application of voriconazole as therapy for Paecilomyces lilacinus, responsible for uncommon devasting fungal keratitis, was effective in infected eyes of rabbits. After 8 days of therapy hyphal masses were present in the control-infected eyes and absent in treated-infected eyes [46].

Ravuconazole (8) is a triazole antifungal related to voriconazole. Its bioavailability ranges from 48-74% in animals and it is highly protein bound. Metabolism is primarily hepatic, and there does not appear to be significant inhibition of CYP3A4 [38]. It is still under clinical development for human use. A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluated the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of on-ychomicosis. A 200 mg/day for 12 weeks was the most effective of the regimens investigated [47]. The in vitro activity of ravuconazole was tested against a collection of 1796 clinical yeast isolates, including fluconazole-susceptible and -resistant strains. Ravuconazole exhibited potent activity with geometric mean MICs of 0.05 mg/ml. It was active against the majority of fluconazole-resistant isolates; but for 102 of 562 (18%) of the resistant isolates, mainly C. tropicalis, C. glabrata, and Criptococcus neoformans, the MICs were > 1 mg/ml [48]. As ravuconazole demonstrates poor aqueous solubility, a water-soluble prodrug was developed for intravenous formulation. BMS-379224 is a phosphonooxymethyl ester derivative of ravuconazole that is rapidly converted into parent drug when infused in animals and healthy humans [49,50]. The pharmacokinetics of ravuconazole was investigated following administration of its produg BMS-379224. It fitted best to a three-compartment pharmacokinetic model. The compound revealed non-linear phar-macokinetics at higher dosages, indicating saturable clearance and/or protein binding. Ravuconazole displayed a long elimination half-life and achieved substantial plasma and tissue concentrations including in the brain.

Albaconazole (9) is a novel triazole derivative related to fluconazole. Its activity was determined in vitro against 12 isolates of C. neoformans and compared with that of fluconazole. Albaconazole was about 100-fold more potent than the reference drug, and showed MICs that ranged from p 0.0012-1.25mg/ml, with MICs for most isolates being between 0.039 and 0.156 mg/ml. An in vivo test performed in infected rabbits showed that albaconazole at dosages ranging from 5 to 80 mg/kg of body weight a day was as effective as fluconazole [51].

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