Synthesis and Antifungal Activities of R-102557 and Related Dioxane-Triazole Derivatives.

Abstract

Novel triazole compounds with a dioxane ring were synthesized. Condensation of the diol precursor 10 with various aromatic aldehydes 11-13 under acidic conditions afforded a series of dioxane-triazole compounds 14-16. The antifungal activities of the compounds 14-16 were evaluated in vivo in mice infection models against Candida and Aspergillus species. High activities were seen for the derivatives with one or two double bond(s) and an aromatic ring substituted with an electron-withdrawing group in the side chain. Among the derivatives, R-102557 (16R: Ar=4-(2,2,3,3-tetrafluoropropoxy)phenyl) showed excellent in vivo activities against Candida, Aspergillus and Cryptococcus species. It also showed high tolerance in a preliminary toxicity study in rats.

New Antifungal 1,2,4-Triazoles with Difluoro(substituted sulfonyl)methyl Moiety.

“…New 1,2,4-triazoles (2) having a difluoro(substituted sulfonyl)methyl moiety were designed and synthesized via key intermediates (3). The introduction of fluorine atoms into the triazole antifungals enhanced their antifungal activities in vitro and in vivo.…”

Design, Synthesis and Antifungal Activity of the Novel Water-Soluble Prodrug of Antifungal Triazole CS-758

“…[7][8][9][10] There have been some efforts to overcome this problem by using a prodrug approach. [11][12][13][14] Previously, we identified CS-758 [15][16][17] which has a broad antifungal spectrum covering Aspergillus spp., FLCZ-resistant Candida spp. and has a good safety profile, including low drug-drug interaction.…”

Synthesis and in Vitro Antifungal Activities of Novel Triazole Antifungal Agent CS-758.

“…1) From such compounds, R-102557 (3d) was chosen as a candidate compound for development on the basis of its in vivo activities in mice. Since it was found that R-102557's high in vivo activities were caused by its excessively long elimination half-life in plasma, 2) we determined to search for a similar compound but with a shorter half-life.…”

“…We reasoned that, even if a compound with good MICs were to exhibit only fair in vivo activities in mice, the compound might still be able to remain sufficiently long in humans to exhibit reasonable therapeutic effects. On this assumption, some of the previous compounds, such as 3b-g, 1) were re-evaluated on the basis of MICs. Their precursor 1a was also submitted for MIC determination.…”

“…Previously, molecular sieves were then used to remove water, 1) but this time we conducted the reaction by concentrating a tetrahydrofuran (THF) solution containing 4, the aldehydes, and p-toluenesulfonic acid in a rotary evaporator. Aldehyde 6j, a precursor of CS-758, was The MICs of the compounds with various side chain lengths were determined against clinically important pathogenic fungi (Table 1).…”