Possible neuroprotective effects of amide alkaloids from <i>Bassia indica</i> and <i>Agathophora alopecuroides</i>: <i>in vitro</i> and <i>in silico</i> investigations

Abstract

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, <i>N-trans</i>-feruloyl-3-methoxytyramine (1), <i>N-trans</i>-feruloyltyramine (2), <i>S</i>-(-)-<i>N-trans</i>-feruloylnormetanephrine (3), <i>S</i>-(-)-<i>N-trans</i>-feruloyloctopamine (4), <i>R</i>-(+)-<i>N-trans</i>-feruloyloctopamine (5), <i>N-trans</i>-caffeoyltyramine (6), and <i>S</i>-(-)-3-(4-hydroxy-3-methoxyphenyl)-<i>N</i>-[2-(4-hydroxyphenyl)-methoxyethyl]acrylamide (7), from <i>B. indica</i> and <i>A. alopecuroides</i>, 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 <i>in silico</i> and modeling analyses (<i>i.e.</i>, 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>i.e.</i>, MAO-B and BACE1). The results indicate that <i>B. indica</i>, <i>A. alopecuroides</i>, and the isolated amide alkaloids might be useful in the development of lead compounds for the prevention of neurodegenerative diseases, especially AD.