In vitro aldose reductase inhibitory activity of 5-benzyl-2,4-thiazolidinediones

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 2; pp. 567 - 574
• Main Authors: Rakowitz, Dietmar, Maccari, Rosanna, Ottanà, Rosaria, Vigorita, Maria Gabriella
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-01-2006; Elsevier Science
• Subjects: 2,4-Thiazolidinediones; Aldehyde Reductase - antagonists & inhibitors; Aldose reductase; ALR2 inhibitors; Biological and medical sciences; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology. Drug treatments; Structure–activity relationships; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology; ALR2 inhibitors; 2,4-Thiazolidinediones; Aldose reductase; Structure–activity relationships; Enzyme; Isozyme; Benzene derivatives; Enzyme inhibitor; Thiazolidinedione derivatives; Acetic acid derivative; In vitro; Structure activity relation; Aldehyde reductase; Aromatic compound; Oxidoreductases; Chemical synthesis; ALR2 inhibitors: Structure-activity relationships
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.08.056

Several 5-benzyl-2,4-thiazolidinediones (
5–
7) were synthesised and tested as in vitro aldose reductase (ALR2) inhibitors. Most of them, particularly N-unsubstituted 5-benzyl-2,4-thiazolidinediones
5 and (5-benzyl-2,4-dioxothiazolidin-3-yl)acetic acids
7, displayed moderate to high inhibitory activity levels. In detail, the insertion of an acetic chain on N-3 significantly enhanced ALR2 inhibitory potency, leading to acids
7 which proved to be the most effective among the tested compounds. In addition, in N-unsubstituted derivatives
5 the presence of an additional aromatic ring on the 5-benzyl moiety was generally beneficial. In fact, the ALR2 inhibition results of compounds
5–
7, compared to those of the previously assayed corresponding 5-arylidene-2,4-thiazolidinediones, indicated that N-unsubstituted derivatives
5b,
c and
d, which bore an additional aromatic group in the para position of the 5-benzyl residue, were significantly more effective than their 5-arylidene counterparts; in all other cases, the saturation of the exocyclic double bond C
C in 5 brought about a moderate decrease in activity.