title: Identification of novel aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold.
abstract: Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.
authors.affiliation: †Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Milan
authors.initials: M
authors.lastname: Stefek
authors.affiliation: †Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Marta
authors.initials: M
authors.lastname: Soltesova Prnova
authors.affiliation: †Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Majekova
authors.affiliation: ‡Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Rechlin
authors.affiliation: ‡Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.affiliation: ‡Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D019342:Acetic Acid / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry* / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; D013438:Sulfhydryl Compounds; C000611863:cemtirestat; D013012:Sorbitol; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase; D019342:Acetic Acid