Secondary Metabolites of the Lichen <i>Lethariella cladonioides</i> and Their Neuroprotective Potential

In the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease, cholinergic neuron dysfunction and neuroinflammation are integral components. Against this backdrop, within the vast array of potential sources under exploration, <i>Lethariella cladonioides</i>, a remarkable lichen with profound ethnopharmacological significance among various Chinese ethnic minorities, has recently emerged as a promising candidate. Through our comprehensive phytochemical investigation, five undescribed diphenylmethanes (<b>1</b>-<b>5</b>), three unreported depsides (<b>6</b>-<b>8</b>), and one novel diphenylether (<b>9</b>), along with 16 known compounds, were successfully isolated and identified. Their structures were elucidated by spectroscopic analysis and X-ray crystallography. Specifically, compounds <b>3</b>-<b>7</b> and <b>9</b> exhibited acetylcholinesterase inhibitory activity, while compounds <b>1</b>, <b>2</b>, and <b>4</b> significantly inhibited NO production by LPS in RAW264.7 cells. Collectively, these findings suggest that <i>L. cladonioides</i> has potential value in preventing and treating neurodegenerative diseases. This potential lies in its ability to potentially retard disease progression or alleviate symptoms by enhancing cholinergic transmission and mitigating neuroinflammation.