Novel Meroterpenoids from <i>Hypericum patulum</i>: Highly Potent Late Na_v1.5 Sodium Current Inhibitors

Abstract

Hypulatones A and B (<b>1</b> and <b>2</b>), two racemic meroterpenoids possessing an unprecedented spiro[benzofuran-2,1'-cycloundecan]-4'-ene-4,6(5<i>H</i>)-dione core, were characterized from <i>Hypericum patulum</i>. Compound <b>2</b> was found to significantly inhibit the late current of Na_v1.5 (late <i>I</i>_Na, IC₅₀ = 0.2 μM). Importantly, <b>2</b> exhibited remarkable separation (>100-fold) of late <i>I</i>_Na relative to peak <i>I</i>_Na and notable selectivity over Ca_v3.1, K_v1.5, and hERG. <b>1</b> showed comparable inhibition on late <i>I</i>_Na compared to that of <b>2</b> with poorer selectivity.