Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3-O-(6′-O-octanoyl)-β-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrug.

白藜芦醇是一种天然存在的1,2-二苯乙烯，作为治疗几种神经退行性疾病的结果已显示出令人鼓舞的结果。然而，由于其低功效和生物利用度，其应用受到限制。在这里，我们设计和合成了烷基化白藜芦醇前药，结合结构修饰以改善抗氧化和抗炎特性，并制备前药以延长药物的生物利用度。为了进行比较，我们还研究了白藜芦醇前药和烷基化白藜芦醇衍生物。甲基化和丁基化的白藜芦醇衍生物在体外显示出最好的神经保护和抗炎活性。这些衍生物的葡糖基和葡糖基酰基前药对斑马鱼胚胎的毒性较低。在对戊四氮挑战的斑马鱼进行神经保护检查时，它们能够恢复神经元损害，但程度要低于白藜芦醇。然而，3- O-（6' - O-辛酰基）-β- d-吡喃葡萄糖苷白藜芦醇（化合物8）的AChE活性恢复超过100％，而白藜芦醇仅高达92％。在亨廷顿氏病的3-硝基丙酸小鼠模型中，白藜芦醇衍生物8通过改善运动活动并防止体重减轻，延缓了发病并降低了HD症状的严重程度。其作用包括与白藜芦醇同等的抗氧化剂，但具有更好的抗炎特性，如脑组织中SOD2的表达和IL-6的循环水平（分别为11 pg / mL和18 pg / mL）所示。最后，化合物8中的辛酰基链可能在炎症和神经元发育中起作用，表明它可能是双重药物而不是前药。