2. Academic Validation
  3. Identification of daurioxoisoporphine D and moringamine I as blood-brain barrier-permeable natural inhibitors of amyloid-β aggregation and neuronal toxicity

Identification of daurioxoisoporphine D and moringamine I as blood-brain barrier-permeable natural inhibitors of amyloid-β aggregation and neuronal toxicity

  • Bioorg Med Chem. 2026 Jul:138:118664. doi: 10.1016/j.bmc.2026.118664.
Hayato Yoshikawa 1,  Emi Yoshida 1,  Takahiro Matsumoto 2,  Kazuma Sugita 1,  Saki Kamiya 1,  Takashi Ohgita 3,  Shinji Kobuchi 4,  Shun Shimohama 5,  Kazuyuki Takata 6
Affiliations

Affiliations

  • 1 Joint Research Laboratory, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
  • 2 Laboratory of Public Health, Division of Biological Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
  • 3 Center for Instrumental Analysis, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
  • 4 Laboratory of Pharmacokinetics, Division of Clinical Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
  • 5 Department of Neurology, Sapporo Medical University, School of Medicine, Sapporo 060-8543, Japan; Jiseikai Hikarigaoka Hospital, Nerima 179-0072, Japan.
  • 6 Joint Research Laboratory, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. Electronic address: [email protected].
PMID: 42008955 DOI: 10.1016/j.bmc.2026.118664
Abstract

Early Alzheimer's disease (AD) is characterized by extracellular accumulation of Amyloid-β (Aβ) peptides and degeneration of basal forebrain cholinergic neurons. Currently, acetylcholinesterase inhibitors and costly anti-Aβ antibodies are used in clinical practice; however, their therapeutic efficacy remains limited. Consequently, disease-modifying therapies that directly target AD pathogenesis and provide neuroprotection-preferably affordable, small-molecule compounds-are urgently needed. To identify seed compounds with potential for clinical translation, screening platforms that accurately recapitulate AD pathophysiology in human-based models are necessary. Therefore, in this study, we employed previously established human induced pluripotent stem cell-derived basal forebrain cholinergic neurons (hiBFChNs). The inhibitory activity against Aβ aggregation was initially evaluated for 129 natural compounds using the thioflavin T assay. Subsequently, the neuroprotective effects of the 65 selected compounds were assessed in human neuroblastoma SH-SY5Y cells and hiBFChNs using the WST-8 and Lactate Dehydrogenase assays as secondary and tertiary screening steps, respectively. Among these, 17 compounds demonstrated both inhibitory effects against Aβ aggregation and neuroprotective effects. Further evaluation of physicochemical properties relevant to brain penetration, together with confirmation of in vitro blood-brain barrier (BBB) permeability using a monkey BBB kit, identified daurioxoisoporphine D and moringamine I as promising seed compounds for AD drug development. Overall, these results indicate that a unified screening platform capable of seamlessly evaluating Aβ aggregation inhibition, neuroprotection, and brain permeability could facilitate the identification of small-molecule therapeutics that modify disease progression in AD.

Keywords

Alzheimer's disease; Cholinergic neurons; Fungus; Human induced pluripotent stem cells; Natural compounds; Plants; Screening.

Figures
Products