Anti-inflammatory Amide–Alkaloid Dimers from the Roots of Piper nigrum L.: Feature-Guided Discovery and Photocatalytic Synthesis

As a traditional medicinal-food ingredient, pepper roots were investigated for bioactive dimeric amide alkaloids. Eighteen pairs of novel anti-inflammatory dimeric amide alkaloids (1a/1b-18a/18b) and two known analogues (19 and 20) were isolated under the guidance of a feature-guided molecular networking (FGMN) strategy, with their structures established by extensive spectroscopic analyses and X-ray diffraction. A visible light photocatalytic method enabled the sustainable synthesis of the dimeric scaffold directly from piperine, a key component of Piper nigrum. In vitro assays demonstrated significant inhibition of NO production in a LPS-induced RAW 264.7 macrophage model. Additionally, dimeric amide alkaloid 21 significantly alleviated skin inflammation, demonstrating bioactivity from a food-derived compound. Overall, this study highlights the potential of P. nigrum roots as a sustainable source of functional alkaloids and establishes a photocatalytic route to skin-health-promoting food ingredients, advancing the valorization of piperine in functional foods.