Quantum Chemical Insights into the Antioxidant Mechanisms of Luteolin and Isorhamnetin: Elucidating Structure-Reactivity Relationships, Pharmacokinetics, and Toxicity for Therapeutic Potential

Abstract

This study presents a comprehensive computational evaluation of the antioxidant properties, physicochemical characteristics, pharmacokinetics, and toxicity profiles of two naturally occurring flavonoids—luteolin and isorhamnetin. Using quantum chemical descriptors and density functional theory (DFT) at the B3LYP/6-31G(d,p) level, we assessed the bond dissociation enthalpy (BDE), adiabatic ionization potential (AIP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE) of both compounds. Isorhamnetin demonstrated superior antioxidant potential, with lower BDE values (79 kcal/mol in vacuum and 71 kcal/mol in water) compared to luteolin (84 and 82 kcal/mol, respectively), suggesting enhanced hydrogen atom donation capacity via the HAT mechanism. Bond order analysis showed higher stability in O3–H1 and O6–H8 bonds (up to 0.773), indicating site-specific reactivity. Pharmacokinetic simulations predicted high gastrointestinal absorption and blood-brain barrier permeability for both compounds, with zero violations of Lipinski, Veber, and Muegge rules. However, toxicity assessments flagged both molecules as mutagenic with medium hERG-related cardiotoxic risk. Notably, isorhamnetin exhibited better aqueous solubility (ESOL class: soluble) than luteolin (moderately soluble), further supporting its potential bioavailability. Overall, isorhamnetin appears to be a more favorable candidate for therapeutic applications, although both require further experimental validation for safety and efficacy.