American Chemical Society, Journal of Medicinal Chemistry, 23(55), p. 10523-10531, 2012
DOI: 10.1021/jm301124s
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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 to treat hyperglycemic-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 anti-oxidant properties, thus emerging as novel multi effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multi functional profile composed by submicromolar ALR2 inhibitory efficacy (IC50: 0.99±0.02 microM), significant and spontaneous NO generation properties and excellent hydroxyl radical scavenging activity. Computational studies on the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series.