Substituted α-Phenyl and α-Naphthlyl-N-tert-butyl Nitrones: Synthesis, Spin-Trapping, and Neuroprotection Evaluation.

ABSTRACT

New derivatives of α-phenyl-N-tert-butyl nitrone (PBN) bearing a hydroxyl, an acetate, or an acetamide substituent on the N-tert-butyl moiety and para-substituted phenyl or naphthlyl moieties were synthesized. Their ability to trap hydroxymethyl radical was evaluated by electron paramagnetic resonance spectroscopy. The presence of two electron-withdrawing substituents on both sides of the nitronyl function improves the spin-trapping properties, with 4-HOOC-PBN-CH2OAc and 4-HOOC-PBN-CH2NHAc being ∼4× more reactive than PBN. The electrochemical properties of the derivatives were further investigated by cyclic voltammetry and showed that the redox potentials of the nitrones are largely influenced by the nature of the substituents both on the aromatic ring and on the N-tert-butyl function. The acetamide derivatives PBN-CH2NHAc, 4-AcNHCH2-PBN-CH2NHAc, and 4-MeO-PBN-CH2NHAc were the easiest to oxidize. A computational approach was used to rationalize the effect of functionalization on the free energies of nitrone reactivity with hydroxymethyl radical as well as on the electron affinity and ionization potential. Finally, the neuroprotection of the derivatives was evaluated in an in vitro model of cellular injury on cortical neurons. Five derivatives showed good protection at very low concentrations (0.1-10 µM), with PBN-CH2NHAc and 4-HOOC-PBN being the two most promising agents.