From Chemical Design to Biological Insight: A Minimal Approach to Evaluate 3,4‐Dimethoxybenzyl‐1,3,4‐oxadiazole Propanamides as Potent 15‐Lipoxygenase Inhibitors with Minimal Cytotoxic Impact

ABSTRACT In our continued efforts in search for 15‐lipoxygenase (15‐LOX) inhibitors as anti‐inflammatory agents, we have designed, synthesized, and characterized a series of new N ‐alkyl/aryl/aralkyl analogs ( 7a‐o ) of 5‐(3,4‐dimethoxybenzyl)‐1,3,4‐oxadiazole propanamide from 3,4‐dimethoxyphenylacetic acid ( 1 ). The analogs ( 7a‐o ) were screened for their inhibitory potential against the soybean 15‐LOX enzyme. The data revealed IC 50 values of all compounds from 3.45 ± 0.27 µM to 28.34 ± 0.85 µM. The potent inhibition was shown by the compounds 7e, 7k, 7i, and 7a with IC 50 values ranging from 3.45 ± 0.27 µM to 4.83 ± 0.39 µM, respectively, as compared to the standard baicalein (IC 50 2.24 ± 0.13 µM) and quercetin (IC 50 4.86 ± 0.14 µM). The analogues 7j, 7 h, 7 g, 7f, 7n, 7m , and 7o also displayed remarkable IC 50 values ranging from 5.21 ± 0.15 µM to 9.37 ± 0.52 µM. During MTT assays, all analogs were nontoxic towards blood mononuclear cells (MNCs) with >75% viability at 0.25 mM tested concentrations. Pharmacokinetic profiles projected good drug‐likeness properties with no violation of the rule of five. Structure‐activity relationship analysis revealed that the position, nature, and number of substituents on the scaffold imparted substantial effects on the inhibition profiles of the target enzyme. Molecular docking studies demonstrated the stabilization of ligand‐receptor complexes employing H‐bonding and hydrophobic interactions. Complexes with 7e and 7c disclosed binding free energy of −9.1 and −8.3 kcal/mol, respectively. Docking studies and DFT calculation data supported the in vitro findings. The work collectively describes 7e, 7k, 7i, and 7a derivatives as leads in the search for anti‐inflammatory agents targeting the 15‐LOX enzyme. Further work on the synthesis of new analogs is in progress.