An extensive study was performed to discover a series of novel 20(R)-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a, exhibited the most potent neuroprotective activity, with an EC₅₀ of 13.17 μM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound 14a at 7.5–120 μM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aβ), β-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1β production; and promoting Aβ_25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10⁻⁶ cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs.

进行了广泛的研究以发现一系列在 3-OH 位置具有各种取代基的新型 20( R )-人参二醇衍生物作为治疗阿尔茨海默氏病的无毒、脑渗透性、多靶点先导物。体外分析表明，带有苄基取代氨基甲酸酯的化合物（我们将其命名为化合物14a）表现出最有效的神经保护活性，EC ₅₀为 13.17 μM。化合物14a的神经保护作用比多奈哌齐略强，比 20( R )-人参二醇强得多。7.5–120 μM 的化合物14a在各种细胞系中表现出低毒性。此外，复合14a表现出广泛的生物学活性，包括抑制细胞凋亡；诱导 tau 过度磷酸化；影响 β-淀粉样蛋白 (Aβ)、β-分泌酶、活性氧、肿瘤坏死因子-α、环氧合酶-2 和白细胞介素-1β 的产生；促进 Aβ _25-35分解。化合物14a穿过血脑屏障的有效渗透率为26.13×10 ^-6  cm/s，表明它可以在中枢神经系统中提供足够的暴露。此外，化合物14a改善了小鼠的学习、记忆和新物体识别，体内毒性实验证实了良好的治疗安全范围。因此，化合物14a是治疗阿尔茨海默氏病的有前途的多功能先导物，并为天然产物衍生的抗阿尔茨海默氏病药物提供了新途径。