Radical scavenging reactivity of β2-agonists: Mechanistic insights into the antioxidant behavior of salbutamol and tulobuterol.

Salbutamol (SAL) and tulobuterol (TUL) are clinically used inhaled bronchodilators belonging to the class of β2-adrenergic agonists. In addition to their bronchodilatory activity, increasing evidence suggests that drug molecules administered to the respiratory tract may interact with reactive oxygen species (ROS) present in the oxidative microenvironment associated with airway inflammation. In this study, the intrinsic radical-scavenging properties of SAL and TUL were investigated using density functional theory calculations at the M06-2X/6-311 + G(d,p) level in the gas phase, as well as in water and methanol. Thermodynamic and kinetic parameters describing hydrogen atom transfer (HAT), single-electron transfer-proton transfer (SET-PT), and sequential proton loss-electron transfer (SPLET) mechanisms were evaluated toward the biologically relevant •OOH radical. Thermodynamic analysis indicates that benzylic C-H bonds in both molecules are more prone to homolytic cleavage than O-H groups, with particularly low bond dissociation enthalpies observed for salbutamol. However, kinetic modelling based on transition state theory with Wigner tunneling corrections identifies the phenolic O-H site of salbutamol as the most reactive position toward •OOH, exhibiting the lowest activation barrier and the highest rate constant. In tulobuterol, which lacks a phenolic group, HAT reactivity is governed by the benzylic C-H position but occurs with higher activation barriers. These results reveal a divergence between thermodynamic preference and kinetic control of radical scavenging and highlight the key role of phenolic functionality in determining the antioxidant behavior of β2-agonists. From a biopharmaceutical perspective, these findings may contribute to a better understanding of the oxidative reactivity and stability of inhaled bronchodilators in pharmaceutical formulations and within the oxidative environment of the respiratory tract.