Improving the metabolic stability of antifungal compounds based on a scaffold hopping strategy: Design, synthesis, and structure-activity relationship studies of dihydrooxazole derivatives.

Abstract

l-amino alcohol derivatives exhibited high antifungal activity, but the metabolic stability of human liver microsomes invitro was poor, and the half-life of optimal compound 5 was less than 5min. To improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of antifungal compounds with a dihydrooxazole scaffold was designed and synthesized. Compounds A33-A38 substituted with 4-phenyl group on dihydrooxazole ring exhibited excellent antifungal activities against C.albicans, C.tropicalis and C.krusei, with MIC values in the range of 0.03-0.25μg/mL. In addition, the metabolic stability of compounds A33 and A34 in human liver microsomes invitro was improved significantly, with the half-life greater than 145min and the half-life of 59.1min, respectively. Moreover, pharmacokinetic studies in SD rats showed that A33 exhibited favourable pharmacokinetic properties, with a bioavailability of 77.69%, and half-life (intravenous administration) of 9.35h, indicating that A33 is worthy of further study.