Antioxidant activity of unexplored indole derivatives: synthesis and screening.

Mónica S Estevão, Luísa C Carvalho, Daniela Ribeiro, Diana Couto, Marisa Freitas, Ana Gomes, L M Ferreira, Eduarda Fernandes, M Manuel B Marques

Index: Eur. J. Med. Chem. 45 , 4869-78, (2010)

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Abstract

The present study envisaged the development of novel antioxidant candidates using the indole scaffold. Several tryptophan and tryptamine derivatives were synthesized, in particular prenylated indole compounds, and their scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) was investigated. The library substitution pattern included several alkyl chains at positions N-1, C-2 of the indole nucleus, including prenyl and isopentyl chain, as well as different groups at the side chain (C-3) that allowed the investigation of a possible radical stabilization. The results obtained showed that tryptophan (8), tryptamine (9), N-phthaloyl tryptamine (5) and N-prenyl tryptophan (13) were the most active against peroxyl radical (ROO(•)) with activities higher than Trolox, which was used as control. The scavenging of hypochlorous acid (HOCl) was also evaluated and tryptophan (8) and tryptamine (9) showed IC(50) of 3.50 ± 0.4 and 6.00 ± 0.60 μM, respectively. Significant activity was also found for the N-prenyl tryptophan (13) with an IC(50) of 4.13 ± 0.17 μM and C-2 prenylated derivative (14), with 4.56 ± 0.48 μM. The studies were extended to RNS and best results were obtained against peroxynitrite anion (ONOO(-)) in the presence of NaHCO(3). N-alkylated tryptophan (18) showed a high activity with an IC(50) of 14.0 ± 6.8 μM. The results show that the tested compounds are effective scavengers of ROS and RNS, and suggest that the radical stabilization is strongly dependent on the type of substituents on the indolic moiety and on their relative positions. In addition, the radical dissipation inside the indolic system is mandatory for the observed antioxidant activity.Copyright © 2010 Elsevier Masson SAS. All rights reserved.