Stereoselective AChE/BChE/BACE1 inhibition by enantiomeric norsesquiterpenoids with an unprecedented oxatricyclo[7.2.1.0(1,9)]dodecane scaffold from the soft coral Sclerophytum humesi.

Chemical investigation of the soft coral Sclerophytum humesi led to the discovery of (±)-norsclerohumin A (1), a pair of enantiomeric norsesquiterpenoids possessing an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold with a rare C5-O-C8 intramolecular ether-bridge. Their structures were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, ECD, and DP4+ analysis. A plausible biosynthetic pathway is proposed to account for the formation of the unique ether-bridged oxatricyclic framework and the generation of the enantiomeric pair (±)-norsclerohumin A. In addition, the absolute configuration of sinunorcaryophyllenol (2) was fully determined for the first time. Mechanistic studies revealed pronounced stereoselective inhibition of acetylcholinesterase (AChE), in which (-)-1b was far more potent than its antipode (+)-1a, with IC values of 10.08 ± 0.48 μM and 149.8 ± 1.02 μM, respectively. Enzyme kinetics showed that (-)-1b is a mixed-type AChE inhibitor K = 6.61 μM, binding both the free enzyme and enzyme-substrate complex. Molecular docking indicated that its ether-bridged oxatricyclic skeleton fits optimally in the AChE active site, stabilizing key interactions within both the catalytic and peripheral binding regions. Importantly, (-)-1b displayed selective AChE inhibition without detectable cytotoxicity toward normal cells (IC > 256 μM), underscoring its favorable safety profile. Furthermore, pharmacokinetic predictions and quantum chemical parameters further suggest favorable drug-like properties, including high gastrointestinal absorption, blood-brain barrier permeability, and low risk of P-glycoprotein/cytochrome P450 interactions. These findings highlight the oxatricyclo[7.2.1.0dodecane scaffold as a promising lead for neurotherapeutic development.