Fluoxetine scaffold to design tandem molecular antioxidants and green catalysts

Abstract

Fluoxetine finds application in the treatment of depression and mood disorders. This selective serotonin-reuptake inhibitor (SSRI) also contrasts oxidative stress by direct ROS scavenging, modulation of the endogenous antioxidant defense system, and/or enhancement of the serotonin antioxidant capacity. We synthesised some fluoxetine analogues incorporating a selenium nucleus, thus expanding its antioxidant potential by enabling a hydroperoxides-inactivating, glutathione peroxidase (GPx)-like activity. Radical scavenging and peroxidatic activity were combined in a water-soluble, drug-like, tandem antioxidant molecule. Selenofluoxetine derivatives were reacted with H₂O₂ in water, and the mechanistic details of the reaction were unravelled combining nuclear magnetic resonance (NMR), electrospray ionisation-mass spectrometry (ESI-MS) and quantum chemistry calculations. The observed oxidation-elimination process led to the formation of seleninic acid and cinnamylamine in a trans-selective manner. This mechanism is likely to be extended to other substrates for the preparation of unsaturated cinnamylamines.

Fig. 1. Fluoxetine and its derivatives studied in this work.

Scheme 1. (a) dimethylamine HCl/HCOH/EtOH; (b) NaBH₄/KOH/MeOH; (c) SOCl₂.

Scheme 2. (d) Mg/Et₂O; (e), Se; (f) NaBH₄/KOH/EtOH; (g) compound 3/EtOH.

Scheme 3. Oxidation of 1-CF₃ and 1-H by H₂O₂. This scheme represents the overall reaction leading to the formation of cinnamylamine and seleninic acid, which were experimentally observed as final products.

Scheme 4. Mechanistic details of selenoxide elimination leading to the formation of selenenic acid and olefin. Selenenic acid undergoes disproportionation and only seleninic acid was experimentally observed.

Fig. 2. ¹H-NMR mechanistic study of the reaction of 1-H with H₂O₂. The graph reported in (a) was obtained by integration of the α-hydrogen signals for the starting material and the two diastereoisomers and the allylic-hydrogens signals for the cinnamylamine in the ¹H-NMR spectra acquired at different time points ( starting material, R–R (and its enantiomer), R–S (and its enantiomer) cinnamylamine 6). In (b), representative ¹H-NMR spectra are reported showing the variation over time during the oxidation-reaction of compound 3, focusing on the region between 4.7 and 3.8 ppm (area of interest to plot the graph; see Fig. S31 for additional spectra).

Scheme 5. Redox equilibrium involving differently oxidised selenium species.

Fig. 3. in the gas phase (a), in benzene (b), and in water (c) for the scavenging of HO˙, HOO˙ and CH₂CHOO˙ from non-aromatic sites of selenofluoxetine. Values for fluoxetine taken from Muraro et al. are showed in a lighter shade for comparison. Level of theory: (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d).

Fig. 4. Fully optimised geometries of intermediates and transition states of the oxidation of selenofluoxetine shown in Scheme 3 (R = H, R′ = CF₃). Reactant and product complexes are omitted for clarity. Level of theory: ZORA-OLYP/TZ2P.

Fig. 5. Energies of the stationary points of the investigated reactions (Scheme 3) for different selenofluoxetine derivatives in the gas-phase (left column) and in water (right column). Level of theory: (COSMO)-ZORA-OLYP/TZ2P.