The
racemic total synthesis of nitrabirine (5) together
with its previously undescribed epimer 2-epi nitrabirine
(5′) is accomplished via a six-step route based
on a biomimetic late-stage heterocyclization. This allowed the assignment
of the relative configuration of nitrabirine by the lanthanide-induced
shifts (LIS) experiment, which was later on confirmed by X-ray diffraction
of obtained single crystals. Furthermore, oxidation studies demonstrated
that the direct N-oxidation of nitrabirine does not
yield nitrabirine N-oxide as reported earlier. In
contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24′, whereas 2-epi nitrabirine (5′) surprisingly leads
to a previously uncharacterized product 22 under the
same conditions. Finally, a Fischer indole reaction gave access to
novel tetracyclic nitrabirine derivatives 26a–d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5′), and all derivatives synthesized in this study revealed general
biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial activities
as well as potent cytotoxic activities.
The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5') is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, later on confirmed by X-ray diffraction of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24' whereas, under the same conditions, 2-epi nitrabirine (5') surprisingly leads to a beforetime uncharacterized product 22. Finally, a Fischer-Indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a-d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5'), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial as well as potent cytotoxic activities.
The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5’) is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, later on confirmed by X-ray diffrac-tion of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24’ whereas, under the same conditions, 2-epi nitrabirine (5’) surprisingly leads to a beforetime uncharac-terized product 22. Finally, a Fischer-Indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a-d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5’), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial as well as potent cytotoxic activities.
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