Theoretical insights into the free radical scavenging mechanisms and metal chelating ability of lobelialsine: a DFT study.

CONTEXT: Lobelialsine is a pyrrolidine alkaloid isolated from Lobelia alsinoides subsp. hancei that exhibits notable antioxidant and anti-inflammatory activities. To elucidate the molecular basis of these biological effects, a comprehensive density functional theory (DFT) study was conducted to investigate its free radical scavenging and metal-chelating properties. Thermodynamic analyses identified the 4'-OH group as the most reactive antioxidant site, exhibiting the lowest bond dissociation enthalpy (82.8 kcal/mol in water and 78.9 kcal/mol in pentyl ethanoate) and proton affinity (33.3 and 60.2 kcal/mol, respectively). The reaction of lobelialsine with the HOO• radical at this position was thermodynamically favorable, with Gibbs free energy changes of - 4.5 kcal/mol in water and  - 5.1 kcal/mol in pentyl ethanoate. Kinetic calculations revealed a pronounced solvent effect, with an overall HOO• scavenging rate constant of 4.91 × 10⁷ M⁻1 s⁻1 in water, substantially exceeding those reported for Trolox and butylated hydroxytoluene (BHT). In addition to its radical-scavenging activity, the monoanionic form of lobelialsine displayed remarkable Cu2⁺-chelating ability, characterized by a highly favorable complexation free energy (ΔG° =  - 17.997 kcal/mol) and a large formation constant (Kf = 4.09 × 1013). These findings suggest that lobelialsine may act as an efficient antioxidant through the combined mechanisms of free radical neutralization and transition-metal sequestration. METHODS: All quantum chemical calculations were performed using the M06-2X/6-311++G(d,p) level of theory implemented in Gaussian 09. Solvent effects were modeled using the SMD continuum solvation approach in water and pentyl ethanoate to represent polar and lipid-like media, respectively. The thermodynamic feasibility of the hydrogen atom transfer (HAT), single-electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) mechanisms was assessed through the calculation of bond dissociation enthalpies (BDEs), ionization potentials (IPs), proton affinities (PAs), and Gibbs free energy changes for reactions with the HOO• radical. Kinetic investigations were conducted using the QM-ORSA protocol combined with transition state theory (TST), including tunneling corrections, to determine activation barriers, branching ratios, and rate constants. The metal-chelating ability of lobelialsine was evaluated by examining the complexation reactions of its neutral, monoanionic, and dianionic forms with hydrated Cu2⁺ ions. The thermodynamic stability of the resulting complexes was characterized through Gibbs free energies of complexation and formation constants derived from optimized geometries and equilibrium calculations.