INTRODUCTION Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic patients but causes severe gastrointestinal side effects. METHODS Systematic structure-activity relationship (SAR) studies using in silico, in vitro and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α- amylase followed by in silico docking studies to identify the binding modes. A lead candidate, FSE 12 was investigated in an STZ mouse model. RESULTS All active FSEs showed desired higher % inhibition of α-glucosidase and desired lower inhibition of α -amylase in comparison to AGI gold standard acarbose. This suggests a greater selectivity of the FSEs towards α -glucosidase than α -amylase, which is proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position and number of the feruloyl substituents on the sucrose core, the aromatic 'OH' group, and the diisopropylidene bridges were key determinants of the % inhibition of α - glucosidase and α -amylase. In particular, the diisopropylidene bridges are critical for achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in vitro results. The molecular docking studies further reveal that the presence of free aromatic 'OH' groups and the substitution at position 3 on the sucrose core are critical for the inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12 was selected as a lead candidate for validation in vivo. The oral co-administration of FSE 12 with starch abrogated the increase in post-prandial glucose and significantly reduced blood glucose excursion in STZ-treated mice compared to control (starch only) mice. CONCLUSION Our studies reveal the potential of FSEs as selective AGIs for the treatment of diabetes, with a hypothetical reduction of side effects associated with commercial AGIs.

中文翻译：

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阿鲁酰蔗糖酯：α-葡萄糖苷酶和 α-淀粉酶的强效和选择性抑制剂。

简介阿魏酰蔗糖酯（FSEs）是一类广泛分布于植物中的苯丙素蔗糖酯（PSEs）。它们被研究为潜在的选择性 α 葡萄糖苷酶抑制剂 (AGI)，以消除与当前商业 AGI 相关的副作用。后者可有效降低糖尿病患者的血糖水平，但会引起严重的胃肠道副作用。方法 使用计算机、体外和体内实验的系统结构-活性关系 (SAR) 研究来实现这一目标。评估 FSE 对淀粉和寡糖消化酶 α-葡糖苷酶和 α-淀粉酶的体外抑制作用，然后进行计算机对接研究以确定结合模式。在 STZ 小鼠模型中研究了主要候选 FSE 12。结果 与 AGI 金标准阿卡波糖相比，所有活性 FSE 都显示出对 α-葡萄糖苷酶的较高抑制百分比和对 α-淀粉酶的较低抑制作用。这表明 FSE 对 α-葡糖苷酶的选择性高于 α-淀粉酶，建议将其用于消除胃肠道副作用。从体外研究来看，蔗糖核心上阿魏酰基取代基的位置和数量、芳香族“OH”基团和二异亚丙基桥是α-葡糖苷酶和α-淀粉酶抑制百分比的关键决定因素。特别是，二异亚丙基桥对于实现抑制选择性至关重要。FSE 的分子对接研究证实了体外结果。分子对接研究进一步揭示了游离芳香族“OH”的存在 基团和蔗糖核心上第 3 位的取代对于两种酶的抑制都是至关重要的。从体外和分子对接研究中，FSE 12 被选为体内验证的主要候选者。与对照（仅淀粉）小鼠相比，在 STZ 治疗的小鼠中，FSE 12 与淀粉的口服共同给药消除了餐后葡萄糖的增加并显着降低了血糖波动。结论 我们的研究揭示了 FSE 作为选择性 AGI 治疗糖尿病的潜力，并假设减少了与商业 AGI 相关的副作用。与对照（仅淀粉）小鼠相比，在 STZ 治疗的小鼠中，FSE 12 与淀粉的口服共同给药消除了餐后葡萄糖的增加并显着降低了血糖波动。结论 我们的研究揭示了 FSE 作为选择性 AGI 治疗糖尿病的潜力，并假设减少了与商业 AGI 相关的副作用。与对照（仅淀粉）小鼠相比，在 STZ 治疗的小鼠中，FSE 12 与淀粉的口服共同给药消除了餐后葡萄糖的增加并显着降低了血糖波动。结论 我们的研究揭示了 FSE 作为选择性 AGI 治疗糖尿病的潜力，并假设减少了与商业 AGI 相关的副作用。