POSTER: Kopsanone and N(4)-oxide-kopsanone: two beta-carbolinic indole alkaloids with monoamine oxidase A inhibitory activity

Indole alkaloids (IAs) are known for their pharmacological activities, including for neurodegenerative diseases (NDs) treatment. In fact, IAs have been calling the attention due to their multifunctionality, interacting with different targets mainly related to NDs. In this study, two β-carbolinic IA (βCIA), namely kopsanone (1) and N(4)-oxide-kopsanone (2), were evaluated for their monoamine oxidase (MAO) inhibitory potential. Both βCIAs were obtained from Aspidosperma macrocarpon. For isolation, the leaves’ methanol extract was submitted to acid-base extraction. The alkaloid fraction (0.47 g) was chromatographed in silica open column using mixtures of CHCl3:MeOH, affording 1 (85 mg) and 2 (14.7 mg). The in vitro assays were carried out using kynuramine as non-selective substrate of human MAO-A and MAO-B supersomes (BD Gentest). Compound 1 was identified based on data comparison to previous studies. Compound 2 analysis, afforded a mass spectrum with a characteristic [M-16]+ fragment and downfield shift in somesignals in NMR analysis, indicating aN-oxide derivative of 1. It was observed that 2 impaired MAO-A activity with an IC50 value of 4.8 μM, while 1 exhibited ten times higher potency. Molecular docking (GOLD, version 5.2, CCDC) was performed aiming at understanding the binding of 1 in MAO-A. Compound 1 was able to bind the MAO-A active site in the same pocket occupied by harmine. Its indole moiety faces to the FAD co-factor, making π-π stacking interactions with Y407. Van der Waals contacts are observed between 1 and Y69, Q215, I335, L337, and F352, contributing to stabilize the protein-ligand complex. The GoldScore retrieved for the docking of 1 in MAO-A was 51.6 while the value obtained for the re-docking of harmine (IC50 = 0.002 μM) was 79.1, suggesting that the in silico scores are in agreement with the experimental data. These results corroborate to the fact that IAs can be used as scaffolds aiming the inhibition of ND related enzymes.