Synthesis, cleavage, and antifungal activity of a number of novel, water-soluble ester prodrugs of antifungal triazole CS-758

• Published in: Bioorganic & medicinal chemistry letters 2009-07, Vol.19 (13), p.3559-3563
• Main Authors: Kagoshima, Yoshiko, Mori, Makoto, Suzuki, Eiko, Shibayama, Takahiro, Iida, Tamako, Kamai, Yasuki, Konosu, Toshiyuki
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological and medical sciences; Candidiasis - drug therapy; CS-758; Humans; Medical sciences; Mice; Microsomes, Liver - metabolism; Parenteral formulation; Pharmacology. Drug treatments; Phosphoryl ester; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Rats; Triazoles - chemistry; Triazoles - pharmacology; Water - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.135

Synthesis and evaluation of some esters of CS-758, as injectable prodrugs, are described. The phosphoryl ester 1a was converted to CS-758 in vivo. In this study, the synthesis and evaluation of a number of esters of CS-758 as injectable prodrugs are described. Phosphoryl ester 1a was soluble in water (>30 mg/mL) and was converted to CS-758 in human liver microsome. It was also converted to CS-758 in rats after iv administration, wherein the bioavailability of CS-758 was 53%. Compound 1a (iv) reduced the viable cell counts in kidneys in a murine systemic Candida albicans infection model, wherein the effect was comparable to or slightly superior to that of CS-758 ( po). The prodrug 1a proved to be a promising injectable antifungal agent whose further evaluation is warranted.