Investigating the potential of prenylated and geranylated acylphloroglucinol-based xanthenones as potent soybean 15-lipoxygenase inhibitors: a combined <i>in vitro</i> and <i>in silico</i> approach

Abstract The 15-lipoxygenase (15-LOX) plays a key role in various diseases associated with inflammation. A geranylated acylphloroglucinol, namely 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, 1 is a natural lead compound which exhibited significant LOXs inhibition. To further improve its 15-LOX inhibitory activity, xanthone moiety was incorporated into its scaffold using molecular hybridization (MH). In vitro soybean 15-LOX inhibition showed that all synthesized hybrids, 8a-c , 9a-c showed 4.5 to 590 times higher activity than tHGA, 1 with IC 50 values ranging from 0.04 to 5.27 µM. Structure activity relationships (SARs) identified that aromatic substitutions (–Cl, –N(C 2 H 5 ) 2 ) on ring C of xanthenone improved activity. The most potent hybrid, 9b exhibited the highest docking score (−10.67 kcal/mol), with molecular dynamics (MD) simulations (100 ns) validating its strong soybean 15-LOX inhibitory potential. The results suggest the therapeutic potential of these LOX inhibitors in inflammation and provide valuable insight and understanding for further structural optimization around the tHGA 1 scaffold.