Synthesis, pharmacokinetics and in vivo antifungal activity of the novel water-soluble prodrugs of itraconazole analogue YL-24

To improve the aqueous solubility of an itraconazole analogue, compound 1 (YL-24), a series of novel prodrugs were synthesized. Among these prodrugs, the phosphate disodium salt compound 7 exhibited excellent aqueous solubility (9.8 mg/mL) at near-neutral pH and sufficient stability in buffer solutions, along with favorable pharmacokinetic profiles. In particular, compounds 1 and 7 provided moderate survival efficacy in murine systemic Candida albicans SC5314 infection model, but their efficacy was weaker than that of fluconazole.