Evaluation of Novel Aminomethyl Indole Derivatives as Src Kinase Inhibitors and Antioxidant Agents

Abstract

Background: Oxidative stress has been implicated in aging and in a variety of diseases affecting the nervous, respiratory, cardiovascular and gastrointestinal system in humans. Reactive oxygen species (ROS) have been associated with mechanisms to activate kinases, such as protein tyrosine kinases, which may initiate malignant transformation. Significant evidences of the activation of protein kinases by oxidative stress brought increased attention to the role of antioxidants in these mechanisms. Therefore, recent efforts have focused on revealing the relationship between protein kinase inhibition and the levels of ROS production. Methods: Antioxidant properties of aminomethyl indole derivatives were investigated by employing various in vitro systems, microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl and scavenging of superoxide anion radical by virtue of superoxide dismutase inhibitory activity. In vitro tyrosine kinase assays of the aminomethyl indole derivatives were evaluated by changes in the enzymatic activity of pp60^c-Src tyrosine kinase through alterations in the phosphorylation level of immobilized kinase substrate. Results: Analysis of the antioxidant effects of indole 1a–c, bromo indole 2a–c and phenyl indole 3a–c derivatives revealed almost equal inhibition against LP for 5-bromo indole 2a–c and phenyl indole 3a–c derivatives and slight inhibition against superoxide dismutase only for 1a and 1c. Nonsubstituted compounds at position 5 showed half-inhibition of LP. Compound 1a has tyrosine kinase inhibition with an IC₅₀ of 102.6 ± 1.16 µM. Conclusion: The substitution feature at position 5 of the indole ring certainly plays an important role in both tyrosine kinase inhibition and antioxidant capacity. While certain lipophilicity of this substitution is important for antioxidant activity, it may, on the other hand, have a negative impact on the inhibition of Src kinase.

Design and synthesis of multipotent 3-aminomethylindoles and 7-azaindoles with enhanced protein phosphatase 2A-activating profile and neuroprotection

“…Gramine has been object of several pharmacological studies, highlighting some of effect on the serotoninergic system [7] or on mitochondrial bioenergetic [8]. Synthetic analogues of 1 have shown pharmacological activities such as antioxidant and antiinflammatory [9,10], anti-serotoninergic [11] or cell Ca 2+ modulators [12]. Moreover, 1 and its analogues have been used as precursors for the synthesis of a huge amount of indole derivatives, taking advantage their easy transformation through a retro-Mannich type reaction in acidic media into intermediates susceptible to smoothly suffer nucleophilic substitutions [13].…”

Anti-osteoclastogenic Effects of Indole Alkaloids Isolated from Barley (Hordeum vulgareVar.Hexastichon) Grass

“…Repeated column chromatography of HVA resulted in the isolation of nine indole alkaloids, including one new compound [hordeumin A ( 1 )] and eight known analogues ( 2 – 9 ) (Figure A). Chemical structures of the eight known alkaloids were identified as 3-(1-pyrrolidiylmethyl)-1 H -indole ( 2 ), (1 H -indole-3-ylmethyl)­(3-methylbutyl)­amine ( 3 ), N , N -bis­(indol-3-ylmethyl)­methylamine ( 4 ), 3-[2-[(indol-3-yl)­methyl]­indol-3-yl]­methylindole ( 5 ), 3,3′-diindolylmethane ( 6 ), gramine ( 7 ), indole-3-carboxaldehyde ( 8 ), and 3-methoxymethylindole ( 9 ) by comparing their physical properties and spectroscopic data with published values in the literature. To the best of our knowledge, this is the first isolation of compounds 2 – 4 from a natural source and compounds 2 – 6 , 8 , and 9 from barley (H.…”

“…3-(1-Pyrrolidiylmethyl)-1 H -indole ( 2 ) was found to be a whitish, amorphous powder. The HR-ESIMS of 2 displayed a protonated molecular ion peak at m / z : 201.1393 [M + H] + (calcd for C 13 H 17 N 2 , 201.1392), indicating a molecular formula of C 13 H 16 N 2 .…”

Prospects of Indole derivatives as methyl transfer inhibitors: antimicrobial resistance managers

“…Protein kinase inhibitors represent an important class of targeted therapeutic agents, particularly as anticancer drugs [37]. Several indoles have been reported to possess kinase inhibition potentials [38][39][40][41]. Also, Indole is reported to be metabolized by human cytochrome P450 2A6 [42] the source of indole could be from tryptophan metabolism by gut microflora.…”