Hemp seed is known for its content of fatty acids, proteins, and fiber, which contribute to its nutritional value. Here we studied the secondary metabolites of hemp seed aiming at identifying bioactive compounds that could contribute to its health benefits. This investigation led to the isolation of 4 new lignanamides, cannabisin M (2), cannabisin N (5), cannabisin O (8), and 3,3'-demethyl-heliotropamide (10), together with 10 known lignanamides, among which 4 was identified for the first time from hemp seed. Structures were established on the basis of NMR, HR-MS, UV, and IR as well as by comparison with the literature data. Lignanamides 2, 7, and 9-14 showed good antioxidant activity, among which 7, 10, and 13 also inhibited acetylcholinesterase in vitro. The newly identified compounds in this study add to the diversity of hemp seed composition, and the bioassays implied that hemp seed, with lignanamides as nutrients, may be a good source of bioactive and protective compounds.

Objectives The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl-and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. Key findings Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. Summary The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.

This study showed that the biological properties of the folk medicinal plants Lycopodium clavatum and Lycopodium thyoides include AChE inhibitory activity and antioxidant effects, two possible mechanisms of action in Alzheimer's related processes.

Indole alkaloids and synthetic indole derivatives are well known for their therapeutic importance. In fact, preclinical and clinical studies had already demonstrated several pharmacological activities for these compounds. Here, we overview the multifunctional potential of these molecules for the inhibition of enzymes related to neurodegenerative disease: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases A and B (MAO-A and MAO-B). A focus will be given on Psychotria L. genus, considering its reported central effects. Finally, three Psychotria alkaloids, namely desoxycordiofoline (61), bahienoside A (64) and bufotenine (65), along with the synthetic indole derivatives (5S)- 5-(1H-indol-3-ylmethyl)imidazolidine-2,4-dione (66), 5-(1H-indol-3-ylmethyl)-2-thioxoimidazolin-4-one (67), 5-(1Hindol- 3-ylmethyl)-3-methyl-2-thioxoimidazolidin-4-one (68), and methyl 2-(aminoN-(2-(4-methylcyclohex-3-enyl)propan- 2-yl)methanethioamino)-3-(1H-indol-3-yl)propanoate (69), were evaluated in vitro regarding their interactions with AChE, BChE, MAO-A and MAO-B. It was observed that 66 and 68 were able to inhibit MAO-A activity with IC50 value of 8.23 and 0.07 μM. Molecular docking calculations were performed in order to understand the interactions between both ligands (66 and 68) and MAO-A. It was observed that the indole scaffold of both compounds bind into the MAO-A active site in the same orientation, establishing van der Waals contacts with lipophilic amino acids. Additionally, the hydantoin ring of 66 is able to interact by hydrogen bonds with two conserved water molecules in the MAO-A active site, while the methyl-thiohydantoin ring of 68 is within hydrogen bond distance from the hydrogen atom attached to the (N-5) of FAD cofactor. Taking together, our findings demonstrate that the indolyl-hydantoin and indolylmethyl-thiohydantoin rings might consists of good scaffolds for the development of new MAO-A inhibitors possessing neuroprotective properties.