No abstract

The synthesis of a series of derivatives of the novel antifungal cyclopeptolide 1, which consists of nine S-amino acids and R-lactic acid, is described. Besides functional group variation of MeAsp4 (esters 2a-d, amides 3a-d, alcohol 4, and its derivatives) and Tyr(Me)9 (demethyl derivative 8, ethers 12a-f, 13, and oxidative degradation of the phenyl group to 14), opening of the lactone by LiOH in THF/H2O allowed manipulation of the hydroxy group of R-Hypr10 in the resulting acyclic peptide 15. Recyclization of 15 under Mitsunobu conditions followed by deprotection led to the S-Hypr10 analogue 17 of 1. Cyclic decapeptides 33 and 34 as well as cyclic undecapeptides 35 and 36 were obtained via the corresponding modified linear peptides 23, 24, 27, and 28 by cyclization. Methylation of all secondary amide groups by CH3I and KH/18crown6 gave the permethylated compound 37. Two of the derivatives (17 and 34) showed superior activities against yeasts in vitro at pH 6.5 as compared to 1, but not at a lower pH (4.5).

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SDZ 89-485 is a new orally and topically active triazole antifungal with efficacy superior to reference compounds in most animal infection models used for preclinical comparison of antifungals.The compound inhibits mycelial transformation of Candida albicans in vitro at MIC50 concentrations of 0.006 and 0.00019 mgl -~ in MEM and NYP medium, respectively.In rodent models of vaginal candidosis SDZ 89-485 was significantly more active than reference compounds after various oral or topical treatment regimens, with ED50 values ranging from 0-09 to 0.79 mgkg -J and 0.01% active ingredient, respectively. When administered orally, the efficacy of SDZ 89-485 was superior to, or as good as that of the reference compounds in several murine models of systemic candidosis, sporotrichosis and histoplasmosis. In murine aspergillosis, using the kidney as the target organ, SDZ 89-485 was as active as itraconazole. Guinea pig trichophytosis was more responsive to oral tluconazole and itraconazole than to oral SDZ 89-485.Fungal infections, particularly systemic mycoses caused by opportunistic pathogens, are a growing problem in patients with impaired immune defence mechanisms and successful therapy of these infections presents difficulties [5,16,20,30,31]. The recently developed triazole antimycotics, fluconazole and itraconazole are under clinical evaluation for the treatment of these mycoses and early results with these drugs look promising [3-7, 12, 19, 22]. SDZ 89-485, a new triazole derivative [11] is the result of a research programme aimed at the development of a new azole-derivative, which has not only an improved antimycotic efficacy but also high selectivity for the target enzyme of fungal sterol biosynthesis [29], and no teratogenic potential [2].The antifungal activity of this compound (Fig. 1) in vitro against a broad spectrum of medically important fungi has already been reported [28]. The minimum inhibitory concentrations (MICs) of SDZ 89-485 against Candida blastospores were consistently within the same range as those of ketoconazole and itraconazole. Since MIC tests targeting yeast blastospores do not accurately reflect the activity of azole antimycotics