Design, synthesis, molecular docking study and biological evaluation of heteroaryl 2-phenoxypyridin-3-yl derivatives as lipoxygenase enzyme inhibitors

Introdution: Lipoxygenase enzyme is responsible for biosynthesis of leukotrienes that possess various pharmacological effects in the body. The beneficial therapeutic effects of lipoxygenase inhibitors have been proved in some diseases such as asthma, cancer and Alzheimer’s disease. So, the lipoxygenase inhibitors could be used in the treatment of some diseases and pathological conditions. In this study, heteroaryl 2-phenoxypyridine-3-yl derivatives have been synthesized and evaluated as lipoxygenase inhibitors. In this basic-applied study, the desired derivatives were synthesized in multiple steps using convenient methods. Then, the structure of compounds was validated using infrared, mass and nuclear magnetic resonance spectroscopy. Finally, lipoxygenase inhibitory activity of compounds was evaluated and molecular docking studies was performed on the most active compound. All target compounds were synthesized in good yields and showed good inhibitory activity against lipoxygenase (IC50 =100-179 mM) in comparison to Quercetin (IC50 = 58.5 mM) as standard inhibitor. The compound 7a (5-(2-phenoxypyridine-3-yl)-1, 3, 4-oxadiazole-2(3H)-thione) showed the most potent activity and the molecular docking studies showed that this compound was well fitted in the active site of enzyme. The synthesized compounds have shown good inhibitory activity against lipoxygenase and the molecular docking studies show that these compounds are able to fit in the active site of enzyme. Therefore, the target compounds could be used as lead compounds for further studies to find novel lipoxygenase inhibitor drugs.