Phenylpropanoids (PPs), a group of natural compounds characterized by one or more C6-C3 units, have exhibited considerable potential in addressing metabolic disease. However, the comprehensive investigation on the relationship of compound structures and involved activity, along with the action mechanisms on the drug target is absent. This study aimed to evaluate the antioxidant and inhibitory activities of 16 PPs against two digestive enzymes, including α-glucosidase and pancreatic lipase, explore the structure–activity relationships and elucidate the mechanisms underlying enzyme inhibition. The findings revealed the similarities in the rules governing antioxidant and enzyme inhibitory activities of PPs. Specifically, the introduction of hydroxyl groups generally exerted positive effects on the activities, while the further methoxylation and glycosylation were observed to be unfavorable. Among the studied PPs, esculetin exhibited the most potent antioxidant activity and dual enzymes inhibition potential, displaying IC values of 0.017 and 0.0428 mM for DPPH and ABTS radicals scavenging, as well as 1.36 and 6.67 mM for α-glucosidase and lipase inhibition, respectively. Quantification analysis indicated esculetin bound on both α-glucosidase and lipase successfully by a mixed-type mode. Further analyses by UV–Vis, FT-IR, fluorescence spectra, surface hydrophobicity, SEM, and molecular docking elucidated that esculetin could bind on the catalytic or non-catalytic sites of enzymes to form complex, impacting the normal spatial conformation for hydrolyzing the substrate, thus exhibiting the weakened activity. These results may shed light on the utilization value of natural PPs for the management of hyperglycemia and hyperlipemia, and afford the theoretical basis for designing drugs with stronger inhibition against the dual digestive enzymes based on esculetin.

中文翻译：

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苯丙素（PP）的抗氧化、抗糖尿病和抗肥胖潜力评估：构效关系和通过综合技术深入了解抗双消化酶的作用机制

苯丙素 (PP) 是一组以一个或多个 C6-C3 单元为特征的天然化合物，在解决代谢疾病方面表现出巨大的潜力。然而，缺乏对化合物结构和相关活性的关系以及对药物靶点的作用机制的全面研究。本研究旨在评估 16 种 PP 对两种消化酶（包括 α-葡萄糖苷酶和胰脂肪酶）的抗氧化和抑制活性，探讨其构效关系并阐明酶抑制的机制。研究结果揭示了 PP 的抗氧化和酶抑制活性规则的相似性。具体而言，羟基的引入通常对活性产生积极影响，而进一步的甲氧基化和糖基化则被观察到是不利的。在所研究的 PP 中，七叶亭表现出最强的抗氧化活性和双酶抑制潜力，清除 DPPH 和 ABTS 自由基的 IC 值分别为 0.017 和 0.0428 mM，抑制 α-葡萄糖苷酶和脂肪酶的 IC 值分别为 1.36 和 6.67 mM。定量分析表明七叶亭通过混合型模式成功地结合到α-葡萄糖苷酶和脂肪酶上。通过UV-Vis、FT-IR、荧光光谱、表面疏水性、SEM和分子对接等进一步分析表明，七叶亭可以与酶的催化或非催化位点结合形成复合物，影响水解底物的正常空间构象，从而表现出活性减弱。这些结果可能揭示天然PPs在高血糖和高脂血症治疗中的利用价值，并为设计基于七叶亭的对双重消化酶具有更强抑制作用的药物提供理论依据。