Benzofuroxane Derivatives as Multi-Effective Agents for the Treatment of Cardiovascular Diabetic Complications. Synthesis, Functional Evaluation, and Molecular Modeling Studies

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• 作者：Stefania Sartini ; Sandro Cosconati ; Luciana Marinelli ; Elisabetta Barresi ; Salvatore Di Maro ; Francesca Simorini ; Sabrina Taliani ; Silvia Salerno ; Anna Maria Marini ; Federico Da Settimo ; Ettore Novellino ; Concettina La Motta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10523-10531
• 全文大小：411K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

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鈥搆,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a鈥搆,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 卤 0.02 渭M), 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鈥揳ctivity relationships of the whole series.