In vitro and in silico insights into the soybean 15-lipoxygenase inhibition with a new C-geranylated chalcone-based flavanone

Abstract

2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is an important molecule found in Melicope pteleifolia and has been reported to exhibit numerous pharmacological activities including LOX inhibition. As part of our continuing effort to search for new 15-sLOX inhibitor with better in vitro efficacies, a C-geranylated chalcone-based flavanone (8) was synthesized via facile Friedel–Crafts acylation followed by direct C-alkylation. The synthesized flavanone was assayed for its in-vitro inhibition against soybean 15-lipoxygenase (15-sLOX); and predicted for its pharmacodynamic and pharmacokinetic properties using docking simulation, SwissADME and PreADMET server. Results indicated that direct C-alkylation on chalcone intermediate using potassium carbonate as base catalyst was possible to establish the conditions that favor the isomerization of chalcone into flavanone. The synthesized flavanone (8) showed better LOX inhibitory activity (IC₅₀: 1.02 ± 0.15 µM) when compared to our previously reported parent compound tHGA (1, IC₅₀: 23.6 ± 1.7 µM) and its chalcone-based analogue (2, IC₅₀: 15.2 ± 1.2 µM). The (R) enantiomer of flavanone (8) showed a good dock score ( −9.97 kcal/mol) which interacts with the target enzyme through one hydrogen bonding, and one hydrophobic interaction with iron-binding amino acid (His 499). Molecular dynamics simulation with 100 ns refined and confirmed the docking study result, and the stability of the complex was verified based on root-mean-square deviation (RMSD), root-mean-square-fluctuation (RMSF), and protein–ligand interaction analyses. The (R) enantiomer of flavanone (8) showed stable hydrophobic and hydrophilic contacts in the active site. This study provides insights into the 15-sLOX inhibitory profile of a C-geranylated chalcone-based flavanone with an electron withdrawing substituents (-F-) at ring B as potent lead.

Graphical Abstract