[Show abstract][Hide abstract] 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 profile. For compounds 5b and 5c, a maximal distribution ratio in a system comprised of 1-octanol/phosphate buffer was recorded near the neutral physiological pH, the region where the isoelectric point lies. Molecular docking simulations into the ALR2 active site performed for the zwitterionic species provided an explanation for the observed structure-activity relationships and the calculated parameters were in agreement with characteristic differences in the stereoelectronic profiles of the tetrahydro- versus hexahydropyridoindoles. 'Drug-likeness' of the novel aldose reductase inhibitors was assessed by applying the criteria of Lipinski's 'rule of five'.