Synthesis and in vitro synergistic antifungal activity of analogues of Panax stipulcanatus saponin against fluconazole-resistant Candida albicans

Abstract

Oleanolic acid 3-O-β-d-glucopyranosyl-(1 → 3)-β-d-glucopyranoside (1) and oleanolic acid 3-O-β-d-glucopyranosyl-(1 → 3)-[α-l-arabinofuranosyl-(1 → 4)]-β-d-glucopyranoside (2), novel Panax stipulcanatus saponin analogues, were synthesized for the first time starting from commercially available oleanolic acid, d-glucose, and L-(+)-arabinose. Glycosyl N-phenyltrifluoroacetimidates as donors and two-step consecutive glycosylation reactions are crucial in the synthesis. In vitro antifungal activity results indicated that analogue 2 combined with fluconazole showed synergistic antifungal activity against fluconazole-resistant Candida albicans, with MIC₅₀ values 31.80 μg/mL and FICI values 0.32. We also found that intermediate compounds 16 and 17 revealed synergistic antifungal activity against susceptible Candida albicans when combined with fluconazole, with MIC₅₀ values 1.43 μg/mL and 1.59 μg/mL, FICI values 0.29 and 0.32, respectively.

Keywords: Fluconazole-resistant Candida albicans; O-glycosylation; Panax stipulcanatus; Saponin analogues; Synergistic antifungal; Synthesis.