Human monoamine oxidase B (hMAO-B) has emerged as a pivotal therapeutic target for Parkinson's disease. Due to adverse effects and shortage of commercial drugs, there is a need for novel, highly selective, and reversible hMAO-B inhibitors with good blood-brain barrier permeability. In this study, a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma, which resulted in the discovery of 75 active compounds, including phenolic acids, volatile oils, and phthalides, two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent, selective, reversible and had good blood‒brain permeability. Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism. Sedanolide (IC = 103 nmol/L; SI = 645) and neocnidilide (IC = 131 nmol/L; SI = 207) demonstrated their excellent potential as hMAO-B inhibitors. They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline. In SH-SY5Y cell assays, sedanolide (EC = 0.962 μmol/L) and neocnidilide (EC = 1.161 μmol/L) exhibited significant neuroprotective effects, comparable to the positive drugs rasagiline (EC = 0.896 μmol/L) and safinamide (EC = 1.079 μmol/L). These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

中文翻译：

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基于在线纳米分级的高通量发现高选择性可逆 hMAO-B 抑制剂

人单胺氧化酶 B (hMAO-B) 已成为帕金森病的关键治疗靶点。由于不良反应和商业药物的短缺，需要新型、高选择性、可逆的、具有良好血脑屏障通透性的hMAO-B抑制剂。本研究建立了川芎提取物的高通量在线纳米分级筛选平台，发现了 75 种活性化合物，包括酚酸、挥发油和苯酞，其中两种是高选择性的新型天然化合物。苯酞 hMAO-B 抑制剂是有效的、选择性的、可逆的并且具有良好的血脑通透性。分子对接和分子动力学模拟阐明了抑制机制。 Sedanolide (IC = 103 nmol/L; SI = 645) 和 neocnidilide (IC = 131 nmol/L; SI = 207) 证明了它们作为 hMAO-B 抑制剂的卓越潜力。它们抵消了与不可逆 hMAO-B 抑制剂（如雷沙吉兰）相关的失活酶的局限性。在SH-SY5Y细胞检测中，景天内酯（EC = 0.962 μmol/L）和新西奈利特（EC = 1.161 μmol/L）表现出显着的神经保护作用，与阳性药物雷沙吉兰（EC = 0.896 μmol/L）和沙非酰胺（EC = 1.079 微摩尔/升）。这些发现强调了景天内酯作为新型天然 hMAO-B 抑制剂的潜力，值得进一步开发为有前途的候选药物。