Design, synthesis, and pharmacological evaluation of heteroaryl thiol-linked kojic acid derivatives as a novel class of acetylcholinesterase inhibitors for Alzheimer's disease therapy.

Natural products have long served as versatile templates for discovering lead molecules against various targets of pharmacological interest. Kojic acid, a fungal metabolite epitomizes this versatility as it elicits broad-spectrum biological properties. Described herein is a series of heteroaryl thiol-linked kojic acid derivatives that demonstrate potent acetylcholinesterase (AChE) inhibition along with anti-amyloid-β (Aβ) aggregation activity and blood brain barrier (BBB) permeability highlighting their potential as a novel class of Anti-Alzheimer's therapeutics. Seventeen kojic acid derivatives, synthesized by incorporating three different heterocyclic thiols, were evaluated for in vitro AChE inhibition employing Ellman's method. The most potent analogs identified from the AChE inhibition studies were further evaluated for binding to the peripheral anionic site (PAS) of AChE using the propidium iodide (PI) displacement assay, anti-amyloid-β (Aβ) aggregation inhibition using the thioflavin T assay, and BBB permeability using the PAMPA-BBB assay. Obtained findings indicated that two compounds Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04295-5.