Modular Approach for the Synthesis and Bioactivity Profiling of 8,8′-Biflavones

In this work, we
report the scalable and modular synthesis
of a
library of 55 monomeric and dimeric flavonoids including 14 8,8′-biflavones.
The sterically demanding tetra-ortho-substituted
axis of an acetophenone dimer key intermediate was constructed in
a regioselective manner using Fe-mediated oxidative coupling. This
step was systematically optimized and performed on up to multigram
scale. The biological activities of this compound library were evaluated,
including cytotoxicity against healthy and malignant human cell lines,
antimicrobial activity against the apicomplexan parasite Toxoplasma gondii, and antioxidant capacity. A marked
increase in activity for the 8,8′-dimeric structures compared
to that of their monomeric counterparts was observed. Several biflavones
were identified with high selectivity indices (low cytotoxicity and
high antiprotozoal activity), showing that this class of natural products
may serve as lead structures for further investigations.