Diabetes mellitus is the major risk factor for cardiovascular disorders. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the pathogenesis of diabetic complications. Accordingly, inhibition of this enzyme is emerging as a major therapeutic strategy for the treatment of hyperglycemia-induced cardiovascular pathologies. In this study, we describe a series of 5(6)-substituted benzofuroxane derivatives, 5a-k,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a-k,m showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multifunctional profile consisting of submicromolar ALR2 inhibitory efficacy (IC50 = 0.99 ± 0.02 μM), significant and spontaneous NO generation properties, and excellent hydroxyl radical scavenging activity. Computational studies of the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series.
|Autori:||Sartini Stefania; Cosconati Sandro; Marinelli Luciana; Barresi Elisabetta; Di Maro Salvatore; Simorini Francesca; Taliani Sabrina; SALERNO S; Marini Anna Maria; Da Settimo Federico; Novellino Ettore; La Motta Concettina|
|Titolo:||Benzofuroxane Derivatives as Multi Effective Agents for the Treatment of Cardiovascular Diabetic Complications. Synthesis, Functional Evaluation, and Molecular Modeling Studies|
|Anno del prodotto:||2012|
|Digital Object Identifier (DOI):||10.1021/jm301124s|
|Appare nelle tipologie:||1.1 Articolo in rivista|