Synthesis, activity, and molecular modeling of new 2, 4-dioxo-5-(naphthylmethylene)-3-thiazolidineacetic acids and 2-thioxo analogues as potent aldose reductase inhibitors.
A series of 2,4-dioxo-5-(2-naphthylmethylene)-3-thiazolidineacetic acids and 2-thioxo analogues have been prepared as aldose reductase inhibitors. In vitro inhibitory activities of bovine lens aldose reductase were determined by a conventional method. 1-Naphthyl-substituted derivatives of the 2-thioxo series were the more potent inhibitors (IC50 congruent with 10 nM) with similar activity to that of Epalrestat. Structural analysis, especially by X-ray crystallography of two selected compounds, and molecular modeling comparisons with Zopolrestat were performed. These results provide explanations of the good activity of the inhibitor, the preference for 1-naphthyl-substituted compounds, and the nature of molecular interactions in these systems.
Fresneau
P
P
Laboratoire de Chimie Thérapeutique and Laboratoire de Chimie Organique, Groupe de Pharmacochimie Moléculaire, EP811-CNRS, France.
Cussac
M
M
Morand
J M
JM
Szymonski
B
B
Tranqui
D
D
Leclerc
G
G
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D052160:Benzothiazoles; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007908:Lens, Crystalline / Q000201:enzymology; D008958:Models, Molecular; D010793:Phthalazines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000085:Acetates; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D010793:Phthalazines; D013844:Thiazoles; C067172:zopolrestat; D000449:Aldehyde Reductase