Five sesquiterpenes were isolated from the dried rhizomes of Acorus calamus var. angustatus Besser. Their structures were determined by spectroscopic analysis and ECD calculations, including one new eudesmane-type sesquiterpene, 2-hydroxy-eudesmane K (1), and four known compounds: eudesmane K (2), isocalamendiol (3), aristolone (4), and axinysone B (5). Their neuroprotective activity was evaluated using an Aβ25–35-induced HT22 cell injury model. Compound 1 showed concentration-dependent neuroprotective activity with an EC50 value of 4.64 µM, whereas the EC50 of positive control resveratrol was 3.23 µM. Compounds 2–4 exhibited neuroprotective activity at effective concentrations of 6.25 μM, 3.12–50 μM and 3.12–12.5 μM, while compound 5 showed no obvious protective effect within the tested concentration range. These results indicate that compound 1 represents a potential lead candidate against neurodegenerative diseases, deserving further investigation.
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