Caracterização eletrônica e redox dos antidepressivos venlafaxina e desvenlafaxina

Abstract

Introduction: Depression is a critical global public health challenge whose pathophysiology is often exacerbated by oxidative stress processes that impair neurotransmitter biosynthesis. This study is justified by the need to understand the redox properties of the antidepressants venlafaxine (VEN) and desvenlafaxine (DES), aiming to correlate their chemical structures with their potential redox effects. Objective: To characterize the electrochemical behavior and anodic oxidation mechanisms of these drugs under different experimental conditions, establishing the relationship between their chemical structures and reactive properties through electroanalytical techniques and computational chemistry. Methods: Electrochemical measurements were performed using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and square-wave voltammetry (SWV) with a carbon paste electrode over a pH range of 3.0 to 9.0. Additionally, electronic structure calculations were carried out using Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT) to evaluate frontier molecular orbitals, molecular electrostatic potential maps, and Gibbs free energy variations. Results and Discussion: Voltammetric analysis revealed irreversible oxidation processes that were strongly pH-dependent, with DES exhibiting maximum current intensity at pH 7.0 and VEN at pH 9.0. DFT calculations confirmed the aromatic ring as the main electron-density site involved in the redox process. In the solvated medium, VEN exhibited a lower vertical ionization potential (7.756 eV) than DES (8.182 eV), due to the inductive effect of the methoxy group. However, DES showed greater experimental ease of oxidation (Epa = 0.66 V vs. 0.81 V for VEN), which was computationally explained by the pronounced thermodynamic stabilization of its phenoxy radical intermediate. The proposed oxidation mechanism for VEN involves oxidative demethylation steps facilitated by the solvent, whereas DES exhibited pronounced adsorptive behavior resulting from the interfacial electropolymerization of its radical species. Conclusion: This study mapped the distinct redox profiles of VEN and DES, demonstrating that the integration of electroanalytical techniques and computational chemistry provides an effective approach for elucidating the reactivity of complex compounds. The findings provide a solid physicochemical basis for understanding the redox behavior of these antidepressants, theoretically supporting their ability to interact directly with and mitigate oxidative stress under biological conditions.