title: Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia.
abstract: The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)-α-aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%.
authors.affiliation: Laboratorio de Radicales Libres y Química Computacional, IQOG, CSIC, Madrid, Spain. samadi@iqog.csic.es
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Elena
authors.initials: E
authors.lastname: Soriano
authors.forename: Julia
authors.initials: J
authors.lastname: Revuelta
authors.forename: Carolina
authors.initials: C
authors.lastname: Valderas
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garrido
authors.forename: Begoña
authors.initials: B
authors.lastname: Bartolomé
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tomassolli
authors.forename: Lhassane
authors.initials: L
authors.lastname: Ismaili
authors.forename: Laura
authors.initials: L
authors.lastname: González-Lafuente
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: María J
authors.initials: MJ
authors.lastname: Oset-Gasque
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy*; D045744:Cell Line, Tumor; D006801:Humans; D006860:Hydrogen Bonding; D017665:Hydroxyl Radical / Q000378:metabolism; D008962:Models, Theoretical; D009589:Nitrogen Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000975:Antioxidants; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; C015388:nitrones; D017665:Hydroxyl Radical