Concise Total Synthesis and Pharmacological Evaluation of Procerones A and B

Procerones are highly brominated marine natural products that were isolated in 2019 from Polycarpa procera. Herein, we report the first total syntheses of procerones A and B, together with their enantiomers, in only three linear steps, starting from commercially available acetophenone and benzaldehyde derivatives. The synthesis takes advantage of a chalcone core structure obtained by Aldol condensation followed by Davis oxidation to implement the chiral α-hydroxy ketone moiety without the use of heavy metals. The effects of all synthesized compounds, including the enantiopure natural products, on the major inhibitory neurotransmitter receptor in the mammalian brain (GABAA receptor) were determined, and the four enantiopure procerones were additionally tested for antiprion activity. While no antiprion activity was observed for the tested compounds, one unprecedented precursor, as well as procerone B and its enantiomer, significantly enhanced GABAA receptor function, suggesting that this scaffold may serve as a starting point for developing novel GABAA receptor modulators.