title: Carboxymethylated pyridoindole antioxidants as aldose reductase inhibitors: Synthesis, activity, partitioning, and molecular modeling.
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'.
authors.affiliation: Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia. exfastfk@savba.sk
authors.forename: Milan
authors.initials: M
authors.lastname: Stefek
authors.forename: Vladimir
authors.initials: V
authors.lastname: Snirc
authors.forename: Paul-Omer
authors.initials: PO
authors.lastname: Djoubissie
authors.forename: Magdalena
authors.initials: M
authors.lastname: Majekova
authors.forename: Vassilis
authors.initials: V
authors.lastname: Demopoulos
authors.forename: Lucia
authors.initials: L
authors.lastname: Rackova
authors.forename: Zelmira
authors.initials: Z
authors.lastname: Bezakova
authors.forename: Cimen
authors.initials: C
authors.lastname: Karasu
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carbone
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000975:Antioxidants; D002243:Carbolines; D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase