Carboxymethylated pyridoindole antioxidants as aldose reductase inhibitors: Synthesis, activity, partitioning, and molecular modeling

Milan Stefek, Vladimir Snirc, Paul-Omer Djoubissie, Magdalena Majekova, Vassilis Demopoulos, Lucia Rackova, Zelmira Bezakova, Cimen Karasu, Vincenzo Carbone, Ossama El-Kabbani

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Abstract

Starting from the efficient hexahydropyridoindole antioxidant stobadine, a series of carboxymethylated tetrahydro- and hexahydropyridoindole derivatives was synthesized and tested for the inhibition of aldose reductase, an enzyme involved in the etiology of diabetic complications. In vitro inhibiton of rat lens aldose reductase was determined by a conventional method. Kinetic analysis of (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (5b) and (2-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (5c), the most potent compounds in this series with activities in micromolar range, showed uncompetitive inhibition. In addition to the importance of the acidic function, the inhibition efficacy was highly influenced by the steric conformation of the lipophilic aromatic backbone when comparing tetrahydro- and hexahydropyridoindole congeners. Selectivity with respect to the closely related aldehyde reductase was determined by measuring the corresponding inhibitory activities. Antioxidant action of the novel compounds was documented in a DPPH test and in a liposomal membrane model, oxidatively stressed by peroxyl radicals. The presence of a basicity center at the tertiary nitrogen, in addition to the acidic carboxylic function, predisposes these compounds to form double charged zwitterionic species, a characteristic which may remarkably affect their pH-lipophilicity pro.
Original languageEnglish
Pages (from-to)4908 - 4920
Number of pages13
JournalBioorganic & Medicinal Chemistry
Volume16
Issue number9
Publication statusPublished - 2008

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