Possible neuroprotective effects of amide alkaloids from Bassia indica and Agathophora alopecuroides : in vitro and in silico investigations.

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.