| Summary: | Lignan phytomolecules demonstrate promising anti-Alzheimer activity by alleviating dementia and preserving nerve cells. The purpose of this work is to characterize the lignans of <i>Anisacanthus virgularis</i> and explore their potential anti-acetylcholinesterase and anti-ageing effects. Phytochemical investigation of <i>A. virgularis</i> aerial parts afforded a new furofuranoid-type lignan (<b>1</b>), four known structural analogues, namely pinoresinol (<b>2</b>), epipinoresinol (<b>3</b>), phillyrin (<b>4</b>), and pinoresinol 4-<i>O</i>-<i>β</i>-<span style="font-variant: small-caps;">d</span>-glucoside (<b>5</b>), in addition to <i>p</i>-methoxy-<i>trans</i>-methyl cinnamate (<b>6</b>) and 1H-indole-3-carboxaldehyde (<b>7</b>). The structures were established from thorough spectroscopic analyses and comparisons with the literature. Assessment of the anticholinesterase activity of the lignans <b>1</b>–<b>5</b> displayed noticeable enzyme inhibition of <b>1</b> (IC<sub>50</sub> = 85.03 ± 4.26 nM) and <b>5</b> (64.47 ± 2.75 nM) but lower activity of compounds <b>2</b>–<b>4</b> as compared to the reference drug donepezil. These findings were further emphasized by molecular docking of <b>1</b> and <b>5</b> with acetylcholinesterase (AChE). Rapid overlay chemical similarity (ROCS) and structure–activity relationships (SAR) analysis highlighted and rationalized the anti-AD capability of these compounds. Telomerase activation testing of the same isolates revealed 1.64-, 1.66-, and 1.72-fold activations in cells treated with compounds <b>1</b>, <b>5</b>, and <b>4</b>, respectively, compared to untreated cells. Our findings may pave the way for further investigations into the development of anti-Alzheimer and/or anti-ageing drugs from furofuranoid-type lignans.
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