🧠 New Kojic Acid-Based Compounds Offer Hope in Alzheimer’s Drug Discovery
Researchers design dual-action inhibitors targeting key Alzheimer’s pathways
Published: June 2025 | Source: 3 Biotech | DOI: 10.1007/s13205-025-04295-5
A team of medicinal chemists from India and Portugal has developed a novel class of compounds based on kojic acid a naturally derived molecule that exhibit promising dual-action activity against two critical pathways in Alzheimer’s disease (AD). Their findings, published in 3 Biotech, could pave the way for next-generation therapeutics that not only improve cognition but also slow the progression of the disease.
🔬 The Scientific Innovation
Alzheimer’s disease is characterized by cholinergic dysfunction (a deficit in acetylcholine, a neurotransmitter essential for learning and memory) and amyloid-beta (Aβ) plaque aggregation, both of which contribute to cognitive decline. Current drugs, like donepezil, target one of these pathways, usually AChE inhibition, but are often limited in their efficacy and tolerability.
To address this, the researchers designed 17 novel derivatives of kojic acid by linking it to various heterocyclic thiols, yielding compounds capable of:
- Inhibiting acetylcholinesterase (AChE) increasing brain acetylcholine levels
- Preventing Aβ aggregation slowing plaque formation
- Crossing the blood-brain barrier (BBB) a crucial hurdle for CNS drugs
Among these, two compoundsMS2MS21–05 and MS21–11 stood out.
🧪 Experimental Highlights
1. In Vitro AChE Inhibition
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| Fig 1: Kojic acid derivatives as acetylcholinesterase inhibitors |
Using Ellman’s colorimetric assay, the team measured AChE inhibition. MS 21–11 showed the strongest inhibition (IC₅₀ = 1.035 μM), followed closely by MS 21–05 (1.225 μM), indicating potency comparable to known drugs.
2. Binding to AChE’s PAS Site
Via a propidium iodide (PI) displacement assay, they confirmed that these compounds also bind to the Peripheral Anionic Site (PAS) of AChE a site linked to Aβ aggregation suggesting dual activity.
3. Aβ Aggregation Inhibition
Using the Thioflavin T assay, both MS 21–05 and MS 21–11 showed moderate inhibition of Aβ fibril formation, in both self-aggregation and AChE-induced models.
4. Blood–Brain Barrier Permeability
Through PAMPA-BBB assays, both compounds demonstrated excellent permeability:
- MS 21–05: Pe = 5.76 × 10⁻⁶ cm/s
- MS 21–11: Pe = 5.94 × 10⁻⁶ cm/s
- Classified as CNS+, they are likely to cross the BBB efficiently.
🖥️ In Silico Studies Confirm Molecular Targets
To further validate their findings, the team used molecular docking and molecular dynamics (MD) simulations.
- MS 21–11 showed strong and stable binding at the active site of hAChE.
- Key interactions included π–π stacking with Phe292 and Tyr334, and hydrogen bonds with Gly117, Gly118, and Glu199.
Its predicted binding free energy (ΔG) was −36.6 kcal/mol, better than that of the reference compound donepezil (−28.9 kcal/mol).
📊 Figure: Structure of Lead Compounds
Fig 2: Predicted molecular interaction diagrams for MS 21–11 in complex with human acetylcholinesterase (hAChE), highlighting π–π interactions and key residues.
Image credit: Moorthy et al., 2025, 3 Biotech
💬 Expert Commentary
"What makes these compounds exceptional is their multitargeted approach—addressing both acetylcholine degradation and amyloid plaque formation. This could lead to better disease-modifying therapies, not just symptomatic relief,"
says Prof. Narayana S. H. N. Moorthy, lead author and medicinal chemist.
🧩 The Road Ahead
While these findings are limited to in vitro and computational models, they open the door to:
- In vivo animal model testing
- Toxicity and pharmacokinetic profiling
- Lead optimization for clinical development
With Alzheimer’s projected to affect 153 million people globally by 2050, such multi-pronged drug candidates may offer real hope for patients and families navigating this devastating disease.
📚 Reference
Moorthy, N.S.H.N. et al. (2025). Design, synthesis, and pharmacological evaluation of heteroaryl thiol-linked kojic acid derivatives as a novel class of acetylcholinesterase inhibitors for Alzheimer’s disease therapy. 3 Biotech, 15:134. https://doi.org/10.1007/s13205-025-04295-5
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