Indole Alkaloids and Semisynthetic Indole Derivatives as Multifunctional Scaffolds Aiming the Inhibition of Enzymes Related to Neurodegenerative Diseases – A Focus on Psychotria L. Genus
Luiz Carlos Klein-Junior, Carolina dos Santos Passos, Aline Pereira Moraes, Vinicius Galvao Wakui, Eduardo Luis Konrath, Alessandra Nurisso, Pierre-Alain Carrupt, Cecilia Maria Alves de Oliveira, Lucilia Kato and Amelia Teresinha Henriques
Affiliation: Programa de Pos Graduacao em Ciencias Farmaceuticas, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, 90610-000 Porto Alegre – RS, Brazil.
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.
Keywords: Cholinesterases inhibition, indole alkaloids, indole derivatives, molecular docking, monoamine oxidases inhibition,
multi-target scaffolds, neurodegenerative diseases, Psychotria.
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