LAUSR

Aims: Morus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti‐Alzheimer's disease (AD) and anti‐glycation potential of moracin derivatives. Main methods: We designed the current study to explore the anti‐AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO− and ABTS·+ radicals, and their anti‐diabetic activity through inhibition of advanced glycation end‐products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer‐assisted drug design and modeling program. Key findings: Among the four Morus‐derived moracins tested, moracin S, which has a prenyl moiety in the 2‐aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose‐dependent fashion, decreased ONOO−‐mediated bovine serum albumin (BSA) nitration and formation of AGEs and amyloid cross‐&bgr; structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues. Significance: The prenyl moiety in the 2‐aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti‐AD drugs. Graphical abstract Figure. No caption available.