Free Radical Scavenging and Antioxidant Activities of Substituted Hexahydropyridoindoles. Quantitative Structure−Activity Relationships

Abstract

New synthetic substituted hexahydropyridoindoles were studied for their radical scavenging ability in a system of an ethanolic solution of alpha,alpha'-diphenyl-beta-picrylhydrazyl and for their lipid peroxidation inhibitory properties in a suspension of unilamellar dioleoylphosphatidylcholine liposomes. The activities in both in vitro systems were correlated with several structural parameters. In the homogeneous system of alpha,alpha'-diphenyl-beta-picrylhydrazyl, the sum of aromatic substitution constants (sigma(+)) and the hydration energy were shown to be effective predictors of the radical scavenging activity of the hexahydropyridoindole derivatives. Moreover, in the heterogeneous system comprising a model liposomal membrane, the overall antioxidant activity of the compounds was affected by their lipid-phase availability governed by the lipophilicity and basicity of the molecules.

Antioxidant action of the hexahydropyridoindole SMe1EC2 in the cellular system of isolated red blood cellsin vitro

“…5,7,[17][18][19][20][21] The molecule center of the antioxidant activity was identified to reside at the indolic nitrogen. 7 Structural alterations in the close proximity of the indolic nitrogen, especially aromatic substitution in positions o and p, were found to influence the antioxidant efficacy.…”

“…7 Structural alterations in the close proximity of the indolic nitrogen, especially aromatic substitution in positions o and p, were found to influence the antioxidant efficacy. 5,7 Moreover, alteration in the synthetically accessible position N2 provides the opportunity to vary basicity and lipophilicity of the compounds, thus modifying bioavailability, without affecting the intrinsic chemical reactivity with free radicals. The subject of this study was SMe1EC2.…”

“…[5][6][7] Modification of the stobadine molecule by aromatic electron-donating substitution was reported to enhance the intrinsic free radical scavenging activity, while variations of the N2 substituent afforded a synthetically accessible way to modulate the biological availability by affecting both lipophilicity and basicity of the molecule, without changing significantly the free radical scavenging activity. [5][6][7] Among the novel derivatives, the compound (±)-cis-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido [4,3-b] indole-2-carboxylic acid ethyl ester (SMe1EC2) (Fig. 1) has been subject of extensive preclinical studies.…”

Stobadine – An Indole Type Alternative to the Phenolic Antioxidant Reference Trolox

“…On the other hand, trolox was found to be much less effective in inhibiting AAPH-induced peroxidation of di-oleoyl-phosphatidylcholine (DOPC) liposomes with respect to stobadine (Rackova et al, 2004;Rackova et al, 2006;Stefek et al, 2008), as exemplified by the respective IC 50 values 25.3 and 93.5 μM, shown in Table 2. Stobadine, in comparison with trolox, more effectively prolonged the lag phase of Cu 2+ -induced low-density lipoprotein (LDL) oxidation measured by diene formation (Horakova et al, 1996).…”

Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship

“…By its splitting, resonance stabilized indolyl radical is created, the stability of which is affected by the presence of aromatic substituents. Electron donor substituents in the positions orto and para facilitate delocalization of the unpaired electron of the indolyl radical and increase its stability (Rackova et al 2006). In the case of 1-indole acetic acid, an optional pathway proposed for the interaction of N-substituted indoles with radicals proceeding via electron donation (Reiter et al 1997;Andreadou et al 2003) is not obviously valid.…”