Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.
Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). The most active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic side chain on N-3 of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery of a very potent ARI (4c), whose activity level (IC50=0.13 microM) was in the same range of Tolrestat. Moreover, the corresponding methyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstituted compounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of N-unsubstituted 2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than the para-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4.
Bruno
G
G
Dipartimento Ch. Inorg., Chim. Anal. e Ch.-Fis, Facoltà Scienze MMFFNN, Università di Messina, Salita Sperone 31, 98166, Messina, Italy.
Costantino
L
L
Curinga
C
C
Maccari
R
R
Monforte
F
F
Nicoló
F
F
Ottanà
R
R
Vigorita
M G
MG
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D048289:Imidazolidines; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D009249:NADP / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D045162:Thiazolidinediones
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007093:Imidazoles; D048289:Imidazolidines; D009281:Naphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; C040550:tolrestat; D009249:NADP; C089946:2,4-thiazolidinedione; D000449:Aldehyde Reductase; C026411:sorbinil