Complex Chalcone Scaffolds from <i>Mallotus philippinensis</i> Fruits as Potential iNOS Inhibitors

The chalcone skeleton is a fundamental structural motif in numerous natural and synthetic compounds, playing a crucial role in various biological activities, including anticancer and anti-inflammatory effects. <i>Mallotus philippinensis</i> is a remarkable source of chalcones, recognized for its diverse chemical structures and significant bioactivity. The presence of complex dimeric chalcones in this species is both characteristic and rare. However, to the best of our knowledge, only five such complex dimeric chalcones have been identified to date. Here, we report six novel complex chalcones, runachalcones A-F (<b>1</b>-<b>6</b>), which significantly expand the chemical space of dimeric chalcones and highlight the untapped structural diversity within <i>M. philippinensis</i> fruits. Their planar structures were elucidated using a combination of NMR spectroscopy and HR-ESIMS, while their absolute configurations were determined through <i>J</i>-based configurational analysis, ROESY spectra, and quantum mechanical calculations of ECD. In an assay using a macrophage line RAW 264.7, only runachalcone F suppressed lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) protein and the production of nitric oxide, suggesting that the compound possesses potential anti-inflammatory properties.