Design, synthesis, and in vitro antifungal and antibacterial evaluation of natural product phloeodictine-based analogs

Our previous work has demonstrated that 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with a C-6 n-tetradecyl side chain based on the natural product phloeodictine scaffold is a new antifungal template. Synthetic analogs by modifying the bicyclic tetrahydropyrrolopyri- midinium skeleton and the N-1 side chain were thus prepared and evaluated for in vitro antifungal activities against the opportunistic fungal pathogens including Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans. Several analogs showed potent activities that were comparable to the antifungal drug amphotericin B, and exhibited low cytotoxicity against mammalian cell lines. Since the phloeodictines were reported to possess antibacterial activities, we also tested these synthetic analogs against clinically relevant bacteria. The Gram-positive bacteria Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Mycobacterium intracellulare were highly susceptible to this class of compounds and several showed potent activities when compared to the antibacterial drug ciprofloxacin. The results indicate that this class of compounds warrants additional studies to identify an appropriate drug lead for preclinical development.