Synthetic heterocyclic scaffolds relevant to human 15-lipoxygenase-2 (h15-LOX-2) inhibition: Scaffold diversity, structure-activity relationships, selectivity challenges, and future directions.

Human 15-lipoxygenase-2 (h15-LOX-2), encoded by the ALOX15B gene, is a non-heme iron-containing dioxygenase implicated in the pathophysiology of atherosclerosis, cancer, and chronic inflammatory disorders through stereospecific oxygenation of arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid, which is subsequently reduced to 15(S)-hydroxyeicosatetraenoic acid. Despite its considerable therapeutic relevance, h15-LOX-2 remains a profoundly underexplored drug target relative to its closely related isozyme, 15-lipoxygenase-1 (15-LOX-1), with which it shares only approximately 38-40% amino acid sequence identity. This fundamental sequence divergence translates into distinct active site architectures, substrate binding profiles, and tissue distribution patterns that strongly justify the pursuit of isoform-selective inhibitor development. Critically, while zileuton remains the sole clinically approved lipoxygenase-targeting drug, it is clinically used as a 5-LOX inhibitor for asthma and is not an h15-LOX-2-targeted therapy. A focused survey of the literature from 2015 to 2025 reveals that no dedicated synthetic medicinal chemistry review exclusively addressing heterocyclic scaffold-based h15-LOX-2 inhibitors currently exists. To address this gap, the present review examines synthetic heterocyclic chemotypes reported as h15-LOX-2 inhibitors or as structurally relevant 15-LOX inhibitory scaffolds, including imidazoles, thiazolidinone-thiadiazole hybrids, triazoles, quinoline-based dual inhibitors, pyrazoles, indoles, benzimidazole hybrids, xanthenones, thienopyrimidines, and isoniazid derivatives. For each scaffold class, synthetic methodologies, in vitro inhibitory potencies, structure-activity relationship analyses, isoform selectivity profiles, and computational docking findings are comprehensively discussed. Cross-scaffold analysis suggests that lipophilicity, a central heteroaromatic anchoring core capable of interacting with His373 and His378, and a geometrically constrained hydrogen-bonding feature oriented toward Ile676 may represent recurring pharmacophoric features associated with potent 15-LOX/h15-LOX-2 inhibition. Among the evaluated chemotypes, imidazole-based derivatives currently demonstrate the strongest h15-LOX-2-directed profile, with IC50 values as low as 0.34 μM and greater than 50-fold selectivity over related lipoxygenase and cyclooxygenase isoforms. Outstanding challenges including the scarcity of ex vivo validated compounds, species-specific translational barriers arising from divergent murine ortholog function, and the absence of wild-type inhibitor co-crystal structures are critically evaluated. Future directions encompassing covalent inhibitor strategies, PROTAC-based targeted degradation, and selective modulation of the pro-ferroptotic h15-LOX-2/PEBP1 complex are discussed as promising avenues to fully realize the therapeutic potential of this target.