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

Abstract

Recently we synthesized a series of dioxane-triazole antifungal agents, which are effective against systemic mycoses.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. In this paper, we will describe the synthesis and in vitro antifungal activities of our new compound CS-758 (3j; former name, R-120758), 3) which is currently under development as an antifungal agent against systemic mycoses.Starting our search, our attention was focused on minimun inhibitory concentrations (MICs) because as the elimination half-life in plasma gets shorter, the requirements for MICs become severer. 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. Some additional compounds, such as 2a, 3a, 3h-j, were prepared.Preparation of the compounds 2a, 3a, 3h-j were done in acetalization reactions of 4 with aldehydes 5a, 6a, 6h-j, respectively (Chart 2). 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 Shinagawa-ku, Tokyo 140-8710, Japan. Received July 9, 2001; accepted September 17, 2001 Synthesis and in vitro antifungal activities of a novel triazole antifungal agent CS-758 (former name, R-120758) are described. The minimum inhibitory concentrations (MICs) of a series of dioxane-triazole compounds related to R-102557 were examined. Variation of the length of the chain between the dioxane ring and the phenyl ring revealed that the linkage with two double bonds is the most preferable. When a cyano group was introduced to the C4 position on the benzene ring, MICs improved further. A fluorine atom was introduced to obtain CS-758. The MICs of CS-758 surpassed those of fluconazole and itraconazole against Candida, Aspergillus and Cryptococcus species. The precursor (E,E)-aldehyde was synthesized stereoselectively from 3-fluoro-4-methylbenzonitrile using the Horner-Wadsworth-Emmons reaction.

1-(2,4-Difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-1-one

“…It is well known that compounds containing the triazole ring have good fungicidal and plant growth-regulating activities (Konosu et al, 2001;Miyauchi et al, 1995;Dyck et al, 2003;Sekimata et al, 2002;Ruel et al, 2003). We report here the crystal structure of the title compound, (I) (Fig.…”

Substituent effect of fluorine atoms in the 2,4-difluorophenyl group on antifungal activity of CS-758

“…Compounds 12a-d were prepared in good yields in a similar manner as that used for the synthesis of CS-758 [23,24]. The synthetic route is shown in Scheme 1.…”

“…The benzylidene protection group was removed by acid treatment in toluene at 50 8C to furnish triols 10a-d. The acetalization reaction between 10a-d and aldehyde 11 [24] afforded 12a-d, respectively. The trans isomers 12a-d, were predominantly produced and easily separated from the cis isomer by silica gel chromatography.…”

“…2), which exhibited excellent antifungal activities against a wide variety of pathogenic fungi [23,24]. CS-758 has good oral absorption, and possesses desirable pharmacokinetic properties [25][26][27][28][29][30][31].…”

1-(4-Bromophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-1-one

“…Many compounds containing a triazole unit have good biological and pharmacological activities, such as antineoplastic, analgesic, antimicrobial and anticonvulsant (Almasirad et al, 2004;Konosu et al, 2001; Baraldi et al, 2002;Ruel et al, 2003). They are widely used in the fields of medication for various diseases and plant protection (Tsuchimori et al, 2002;Patchett & Nargund, 2000;Tafi et al, 2002;Sekimata et al, 2002).…”