Structure–activity relationships and molecular modelling of 5-arylidene-2,4-thiazolidinediones active as aldose reductase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 8; pp. 2809 - 2823
• Main Authors: Maccari, Rosanna, Ottanà, Rosaria, Curinga, Carmela, Vigorita, Maria Gabriella, Rakowitz, Dietmar, Steindl, Theodora, Langer, Thierry
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-04-2005; Elsevier Science
• Subjects: 2,4-Thiazolidinediones; Aldehyde Reductase - antagonists & inhibitors; Aldose reductase; Animals; Biological and medical sciences; Cattle; Crystallography, X-Ray; Diabetes mellitus; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Lens, Crystalline - enzymology; Medical sciences; Models, Molecular; Molecular modelling; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship; Thiazolidinediones - chemical synthesis; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology; 2,4-Thiazolidinediones; Molecular modelling; Aldose reductase; Diabetes mellitus; Endocrinopathy; Enzyme; Active site; Prediction; Enzyme inhibitor; Thiazolidinedione derivatives; Acetic acid derivative; In vitro; Modeling; Structure activity relation; Molecular model; Aldehyde reductase; Aromatic compound; Oxidoreductases; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.02.026

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The structure–activity relationships (SARs) of 5-arylidene-2,4-thiazolidinediones active as aldose reductase inhibitors (ARIs) were extended by varying the substitution pattern on the 5-arylidene moiety and on N-3. In particular, the introduction of an additional aromatic ring or an H-bond donor group on the 5-benzylidene ring enhanced ALR2 inhibitory potency. Moreover, the presence of a carboxylic anionic chain on N-3 was shown to be an important, although not essential, structural requisite to produce high levels of ALR2 inhibition. The length of this carboxylic chain was critical and acetic acids
4 were the most effective inhibitors among the tested derivatives. Molecular docking simulations into the ALR2 active site accorded with the in vitro inhibition data. They allowed the rationalization of the observed SARs and provided a pharmacophoric model for this class of ARIs.