| Summary: | Three new flavonoid derivatives, melodorones A–C (<b>1</b>–<b>3</b>), together with four known compounds, tectochrysin (<b>4</b>), chrysin (<b>5</b>), onysilin (<b>6</b>), and pinocembrin (<b>7</b>), were isolated from the stem bark of <i>Melodorum fruticosum.</i> Their structures were determined on the basis of extensive spectroscopic methods, including NMR and HRESIMS, and by comparison with the literature. Compounds <b>1</b>–<b>7</b> were evaluated for their in vitro α-glucosidase inhibition and cytotoxicity against KB, Hep G2, and MCF7 cell lines. Among them, compound <b>1</b> exhibited the best activity against <i>α</i>-glucosidase and was superior to the positive control with an IC<sub>50</sub> value of 2.59 μM. On the other hand, compound <b>1</b> showed moderate cytotoxicity toward KB, Hep G2, and MCF7 cell lines with the IC<sub>50</sub> values of 23.5, 19.8, and 23.7 μM, respectively. These findings provided new evidence that the stem bark of <i>M. fruticosum</i> is a source of bioactive flavonoid derivatives that are highly valuable for medicinal development.
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