title: Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies.
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.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Silvia
authors.initials: S
authors.lastname: Salerno
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy*; D048909:Diabetes Complications / Q000188:drug therapy*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D051381:Rats; D010069:Oxadiazoles
chemical_list: D001583:Benzoxazoles; C014354:benzofuroxan; D010069:Oxadiazoles