Beyond Empirical Trends: Density Functional Theory-Based Nuclear Magnetic Resonance Analysis of Mono-Hydroxyflavone Derivatives

Flavone derivatives have emerged as promising antiviral agents, with baicalein demonstrating the potent inhibition of the SARS-CoV-2 main protease (Mpro). In this study, the unique electronic and structural properties of 3-hydroxyflavone (3-HF) were investigated using the density functional theory (B3PW91/cc-pVTZ), providing insights into its potential as a bioactive scaffold. Among mono-hydroxyflavone (n-HF) isomers, 3-HF exhibits an extensive intramolecular hydrogen-bonding network linking the phenyl B-ring to the A- and γ-pyrone C-rings, enabled by the distinctive C3-OH substitution. Despite a slight non-planarity (dihedral angle: 15.4°), this hydrogen-bonding network enhances rigidity and influences the electronic environment. A 13C-NMR chemical shift analysis revealed pronounced quantum mechanical effects of the C3-OH group, diverging from the trends observed in other flavones. A natural bond orbital (NBO) analysis highlighted an unusual charge distribution, with predominantly positive charges on the γ-pyrone C-ring carbons, in contrast to the typical negative charges in flavones. These effects impact C1s orbital energies, suggesting that the electronic structure plays a more significant role in 13C-NMR shifts than simple ring assignments. Given the established antiviral activity of hydroxylated flavones, the distinct electronic properties of 3-HF may enhance its interaction with SARS-CoV-2 Mpro, making it a potential candidate for further investigation. This study underscores the importance of quantum mechanical methods in elucidating the structure–activity relationships of flavones and highlights 3-HF as a promising scaffold for future antiviral drug development.