Imidazole antimycotics

Heeres J, Backx LJ, Mostmans JH, Van Cutsem J (1979) Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J Med Chem 22 1003-1005... 

Clotrimazole. The imidazole derivative clotrimazole (6) was iatroducedia 1969. Clotrimazole [23593-75-1] or l-((9-chloro-a,a-diphenylbenzyl)imidazole is a water-iasoluble antimycotic for topical appHcation, with a broad-spectmm activity against mycoses of the skin and the vagiaa. 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Other imidazole derivatives include clotrimazole (Fig. 5.20B), miconazole (Fig. 5.20C) and econazole (Fig. 5.20D), all of which possess a broad antimycotic spectrum... 

Bonazzi et al. [18] reported the determination of miconazole and other imidazole antimycotics in creams by supercritical fluid extraction and derivative ultraviolet spectroscopic method. Cream based pharmaceuticals were mixed with celite and anhydrous sodium sulfate and extracted by supercritical fluid extractor (SFE) with... 

Kublin and Kaniewska [52] used a gas chromatographic method for the determination of miconazole and other imidazole antimycotic substances. The conditions have been established for the quantitative determination of miconazole and the other drugs, which are present in pharmaceuticals such as ointments and creams. The column, packed with UCW-98 on Chromosorb WAW, and flame-ionization detector were used. The statistical data indicate satisfactory precision of the method, both in the determination of imidazole derivatives in substances and in preparation. 

In the four-membered rings, the P-lactam moiety is part of the classical penicillin and cephalosporin antibiotics. The most prominent example of a drug with a five-membered ring with one nitrogen atom is Lipitor (see Table 1.1). In the five-membered rings with 2 N atoms, imidazoles are found both in modern agrochemicals, especially the imidazolinones (e.g., Imazapyr), and pharmaceuticals, such as antimycotics (e.g., isoconazole, ketoconazole, and... 

Clotrimazole, is an imidazole derivative and has a broad antimycotic spectrum of action in vivo, which includes dermatophytes, yeasts, moulds etc. 

The utility of some of these products for side-chain modification has also been demonstrated. For example, 4-chloro-3-formylpyridine undergoes the Hantzsch reaction to give a 4-(3-chloropyridine)-l,4-dihydropyridine derivative (88%). (4-Chloro-3-pyridyl)diphenylmethanol affords aza-analogues (65-70%) of the antimycotic agent chlortrimazol by reaction with thionyl chloride and imidazole derivatives (88JHC81). 

Apart from the triazole derivatives, a small group of imidazoles is active against plant pathogens (Figure 5). The most important compounds in this group are imazalil and prochloraz. However, most of the Important antimycotic EBI s originate from the imidazole series. Two of these antimycotics are bifonazole and clotrimazole, which resemble fluotrimazole. These two antimycotics will be dis-... 

Upon reaction with N,N -thionyldiimidazole, isatin and 1-methylisatin furnish the substitution product resulting from the addition of two imidazole groups at position C-3. These compounds where found to possess antimycotic activity312 (Scheme 72). 

Dooms-Goossens A, Matura M, Drieghe J, Degreef H. Contact allergy to imidazoles used as antimycotic agents. Contact Dermatitis 1995 33(2) 73-7. 

Yoneyama E. [Allergic contact dermatitis due to topical imidazole antimycotics. The sensitizing ability of active ingredients and cross-sensitivity.] Nippon Ika Daigaku Zasshi 1996 63(5) 356-64. 

Other imidazole derivatives include clotrimazole (Fig. 10.22B), miconazole (Fig. 10.22C) and econazole (Fig. 10.22D), all of which possess a broad antimycotic spectrum with some antibacterial activity and are used topically. Miconazole is used topically but can also be administered by intravenous or intrathecal injection in the treatment of severe systemic or meningeal fungal infections. Newer imidazoles are (a) ketoconazole (Fig. 10.22E),... 

Bonazzi D, Cavrini V, Gatti R, Boselli E, Caboni M. Determination of imidazole antimycotics in creams by supercritical-fluid extraction and derivative UV spectroscopy. J Pharm Biomed Anal 1998 18 235-240. 

Terbinafme (TBF) as an allylamine was purchased from Wako pure chemical (Osaka, Japan). Ciclopirox olamine (CPO), and four imidazole antimycotics, including miconazole (MCZ), bifonazole (BFZ), sulconazole (SCZ) and clotrimazole (CTZ) were purchased from Sigma (St. Louis, MO, USA). Amorolfin (AMF) was synthesized in our laboratories and identified by nuclear magnetic resonance. These agents were dissolved in dimethyl sulfoxide (DMSO) at various concentrations and added at a final concentration less than 1%. 

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

Developmental Topical Antimycotics. Most of the topical antimycotics still being developed are azole derivatives (mostly imidazole), including butoconazole, oxiconazole, omoconazole, zinoconazole, and sulconazole (Fig. 3). Generally speaking, these newer azoles offer no additional therapeutic advantages compared to existing substances. These drugs are already available in certain countries, but are not yet commercialized on a worldwide scale. 

Extensive SAR studies showed that the imidazole ring is crucial for broad-spectrum, high-potency antimycotic activity in vivo. It is ironic that even replacement with benzimidazole, the original lead compound, exhibited very low effectivness. Exchanging one nitrogen with carbon (i.e., pyrazoles and piperazines) also resulted in less active, or even inactive, compounds. 

Inhibition of human aromatase by imidazole drugs has been extensively studied in vitro and in vivo [56, 115-120]. Ketoconazole has been most widely studied due to its widespread clinical use as an orally active broad-spectrum antimycotic and reports of associated gynaecomastia [109]. In vitro, it inhibits the aromatisation of both androstenedione [56] and testosterone [118], but is slightly less effective than AG (for example, K, values with androstenedione as substrate are 6,000 nM for ketoconazole and 4,400 nM for AG [56]). In contrast to AG, ketoconazole has been reported to be a non-competitive inhibitor of aromatase [116], although inhibition of other steroid hydroxylases is apparently competitive in nature [114] some other azoles such as miconazole have been reported to be competitive inhibitors [56]. 

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