Dual COX‐2/5‐LOX Inhibition by Novel Thymol Derivatives: From Molecular Modeling to In Vitro Validation

Dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) inhibitors constitute safer alternatives to classical nonsteroidal anti-inflammatory drugs, widely used to effectively manage inflammation. In this article, molecular docking and molecular dynamics simulations guide the synthesis of novel thymol derivatives that interact with both COX-2 and 5-LOX active sites. Ligands are designed with the aim of improving thymol bioactivity, selectivity, stability, as well as pharmacokinetic properties. Therefore, –Br, –F, and –CF3 inclusion on thymol is here evaluated, screening COX-2 and 5-LOX interactions with thymol (T), 4-fluorothymol (FT), 4-bromothymol (BT), isopropyl thymyl succinate (T1), 1,1,1,3,3,3-hexafluoroisopropyl thymyl succinate (T2), and 1′,1′,1′,3′,3′,3′-hexafluoroisopropyl 4-(4′’-thymyl)-4-oxobutanoate (T3). Molecular modeling reveals that the estimated ligands can establish favorable interactions with both COX-2 and 5-LOX active pockets, highlighting T1–T3 as the most promising compounds. In vitro assays identify T3 as the most active COX-2 inhibitor, while T2 results as the most effective ligand for 5-LOX. Interestingly, cavity analysis of the COX-2 entry site reveals that T3 insertion is favored over T1 and T2 due to its greater polarity, conferred by the presence of a free phenolic group (OH) able to establish H-bonds with surrounding residues.