Combating oxi-inflamm-aging: Passerini adducts tethered with 1,2,3-triazoles for enhanced antioxidant defense and 5-LOX inhibition

Oxi-inflamm-aging, a term describing the interplay between chronic oxidative stress and inflammation, is a key contributor to cellular deterioration and age-related diseases (ARDs). To target these interconnected mechanisms, we designed and synthesized novel hybrids of Passerini adducts tethered with 1,2,3-triazoles, inspired by the naturally isolated dipeptide aurantiamide acetate known for its dual anti-inflammatory and antioxidant properties. The adducts were synthesized <i>via</i> an optimized one-pot reaction of 4-nitrophenylisonitrile, cyclohexanone, and appropriate carboxylic acids under Passerini three-component reaction (Passerini-3CR) conditions, followed by the installation of structurally diverse 1,2,3-triazoles onto the α-acyloxy carboxamides through click chemistry. Biological evaluation demonstrated that all the derivatives exhibited significant antioxidant activity, outperforming ascorbic acid in the TBARS assay. Similarly, the nitric oxide (NO) assay showed strong activity for most compounds, except 11, 12, and 17. Notably, compounds 7, 8, 15, and 18 exhibited potent 5-LOX inhibition, with 18 and 15 surpassing quercetin's activity by ∼1.6-fold. In the RBC membrane stabilization assay, compound 18 emerged as the most potent, indicating strong anti-inflammatory potential. A conformational analysis of compound 4 was conducted, revealing that conformer 4c is the most stable in the gas phase, whereas 4d dominates in polar solvents due to hydrogen bonding interactions, which might influence bioactivity. Molecular docking studies elucidated key binding interactions of compounds 15 and 18 within the 5-LOX active site, supporting their observed inhibitory profiles. Furthermore, <i>in silico</i> ADMET profiling confirmed favorable drug-like properties for these hits, suggesting their potential as probable candidates for combating oxi-inflamm-aging.