In Alzheimer's disease (AD), the accumulation of amyloid-β plaques, overactivity of MAO-B, and phosphorylated tau protein in the central nervous system result in neuroinflammation and cognitive impairments. Therefore, the multi-targeting of these therapeutic targets has emerged as a promising strategy for the development of AD treatments. The current study reports the isolation and identification of seven amide alkaloids, namely, N-trans-feruloyl-3-methoxytyramine (1), N-trans-feruloyltyramine (2), S-(-)-N-trans-feruloylnormetanephrine (3), S-(-)-N-trans-feruloyloctopamine (4), R-(+)-N-trans-feruloyloctopamine (5), N-trans-caffeoyltyramine (6), and S-(-)-3-(4-hydroxy-3-methoxyphenyl)-N-[2-(4-hydroxyphenyl)-methoxyethyl]acrylamide (7), from B. indica and A. alopecuroides, which are halophytic plants that have been reported to contain diverse phytochemicals. Additionally, the study explores the potential inhibition effects of the isolates on β-secretase, monoamine oxidase enzymes, and phosphorylated tau protein, and their anti-aggregation effects on amyloid-β fibrils. Compounds 1, 2, and 7 showed potent inhibitory activity against BACE1, MAO-B, and phosphorylated tau protein, as well as anti-aggregation activity against Aβ-peptides. Additionally, compound 6 displayed promising inhibition activity against MAO-B enzyme. Further in-depth in silico and modeling analyses (i.e., docking, absolute binding free energy calculations, and molecular dynamics simulations) were carried out to reveal the binding mode of each active compound inside the corresponding enzyme (i.e., MAO-B and BACE1). The results indicate that B. indica, A. alopecuroides, and the isolated amide alkaloids might be useful in the development of lead compounds for the prevention of neurodegenerative diseases, especially AD.
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