Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors.
Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel aldose reductase (ALR2) inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.
Da Settimo
Federico
F
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Primofiore
Giampaolo
G
La Motta
Concettina
C
Sartini
Stefania
S
Taliani
Sabrina
S
Simorini
Francesca
F
Marini
Anna Maria
AM
Lavecchia
Antonio
A
Novellino
Ettore
E
Boldrini
Enrico
E
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002386:Cataract / Q000209:etiology / Q000517:prevention & control; D018360:Crystallography, X-Ray; D005693:Galactosemias / Q000150:complications; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000085:Acetates; D009281:Naphthalenes; D013844:Thiazoles; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase