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.