Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies

Journal of Medicinal Chemistry
Stefania SartiniConcettina La Motta

Abstract

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.

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Citations

Aug 14, 2013·Journal of Agricultural and Food Chemistry·Lili WangYonghao Ye
Jul 9, 2014·Evidence-based Complementary and Alternative Medicine : ECAM·Junjun ChenYueqin Wang
Oct 15, 2014·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Sarah Fernandes TeixeiraAdilson Kleber Ferreira
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Sep 2, 2020·European Journal of Medicinal Chemistry·Antonios KousaxidisAthina Geronikaki

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