5-Lipoxygenase Inhibition in Inflammatory Disorders

5-Lipoxygenase (5-LOX) catalyses the conversion of arachidonic acid into leukotrienes, potent lipid mediators that drive leukocyte recruitment, vascular permeability and bronchoconstriction in diverse inflammatory settings. Overproduction of leukotrienes contributes to the pathogenesis of asthma, atherosclerosis, rheumatoid arthritis and other chronic inflammatory diseases. Inhibition of 5-LOX therefore represents a validated therapeutic strategy to mitigate tissue damage, oedema and pain associated with uncontrolled inflammation. The only clinically approved 5-LOX inhibitor, zileuton, shows efficacy in asthma but is limited by hepatic side effects and variable patient response. Recent research has concentrated on designing novel inhibitors with improved potency, selectivity and metabolic stability. Structural classes under investigation include hydroxycinnamic acid esters, phenolic ketone derivatives and hybrid molecules that target both the catalytic iron centre and the surrounding active‐site pocket. Advances in structure–activity relationship studies and molecular docking have revealed critical interactions—such as π–π stacking with aromatic residues and modulation of redox mechanisms—that guide rational drug discovery. Preclinical models in isolated leukocytes and whole‐blood systems confirm the promise of next‐generation 5‐LOX inhibitors to suppress leukotriene biosynthesis more effectively and safely, heralding new avenues for anti-inflammatory therapy.

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5-Lipoxygenase Inhibition in Inflammatory Disorders publication trend

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Technical terms

5-Lipoxygenase (5-LOX): An iron-dependent enzyme that oxygenates arachidonic acid to form leukotriene precursors.

Leukotrienes: Bioactive lipids derived from arachidonic acid that promote vasodilation, vascular permeability and immune cell migration.

Zileuton: A hydroxyurea-based 5-LOX inhibitor approved for asthma, limited by hepatotoxicity and variable efficacy.

Caffeic Acid Phenethyl Ester (CAPE): A natural polyphenol that inhibits 5-LOX and leukotriene biosynthesis, used as a scaffold for synthetic analogues.

Hydroxycinnamic Acid Esters: Phenolic compounds derived from cinnamic acid, employed to design potent and stable 5-LOX inhibitors.

References

1. New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition. Molecules (2020).
2. Phenolic acid phenethylesters and their corresponding ketones: Inhibition of 5‐lipoxygenase and stability in human blood and HepaRG cells. Pharmacology Research & Perspectives (2019).
3. Caffeic Acid Phenethyl Ester and Its Amide Analogue Are Potent Inhibitors of Leukotriene Biosynthesis in Human Polymorphonuclear Leukocytes. PLOS ONE (2012).