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

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.

Graphical abstractSynthesis and evaluation of some esters of CS-758, as injectable prodrugs, are described. The phosphoryl ester 1a was converted to CS-758 in vivo.Figure optionsDownload full-size imageDownload as PowerPoint slide