Beyond Bioactivity: Conformational Effects on the Electronic and Optical Properties of the Anti-Inflammatory Alkaloid Oleradiazahyde

Introduction

Oleradiazahyde is a recently reported alkaloid with anti-inflammatory activity. It was isolated from Portulaca oleracea, an edible and medicinal plant widely distributed in tropical and subtropical regions and long used in traditional medicine. The flexible hydroxyethyl substituent of oleradiazahyde raises a question concerning its molecular characterization: to what extent can a single geometry represent its electronic and optical behavior in aqueous solution? This study investigates the effects of conformational heterogeneity on these properties.

Methods

An extensive GOAT/GFN2-xTB/ALPB(water) search generated 268 candidate structures, which were clustered into nine representatives. These structures were optimized using r²SCAN-3c/SMD(water) and PBE0-D4/def2-TZVP/SMD(water), and both DFT levels produced the same energetic ordering. Harmonic frequency calculations verified the six lowest PBE0 conformers as minima. TD-PBE0/def2-TZVP calculations and natural transition orbital (NTO) analysis were performed for the three dominant conformational families.

Results

The six lowest conformers are distributed among three dominant families with estimated populations of approximately 75, 20, and 5%. Conformational variation substantially changes the molecular dipole moment, which ranges from 1.21 to 4.54 D, while the Kohn–Sham HOMO–LUMO gap varies only from 3.21 to 3.29 eV. The weak lowest singlet excitation occurs between 527 and 556 nm (f = 0.014–0.028). By contrast, a stronger fourth singlet transition remains between 279 and 283 nm (f = 0.306–0.326) and is dominated by a single NTO pair in all three families.

Conclusions

Conformational heterogeneity has a pronounced effect on the ground-state polarization of oleradiazahyde, but a more limited influence on its frontier-orbital gap and stronger UV transition. The results indicate that different electronic and optical properties respond differently to conformational rearrangement and provide an ensemble-based description of the physicochemical behavior of this recently identified bioactive natural product.