Synthesis and biological evaluation of branched N1 functionalized lophine-pyrazole heptacycles as myeloperoxidase inhibitors and anti-inflammatory agents.

Myeloperoxidase (MPO)-derived oxidants play a critical role in endothelial dysfunction and the progression of inflammatory disorders. Herewith, we present the construction of branched N1 functionalized lophine-pyrazole heptacyclic frameworks (7ae-7di) via successive reductive activation of sp 2 carbon with concomitant cyclocondensation as potential MPO inhibitors and anti-inflammatory agents. From MPO inhibition assay and ex vivo anti-inflammatory studies, 7di emerged as a promising lead with an IC50 of 13.71 ± 0.41 μM and 9.86 ± 0.31 μM, respectively. The lead compound 7di exhibited potential anti-inflammatory efficacy in an in vivo carrageenan-induced paw edema model. Molecular dynamics simulations revealed stable protein-ligand interactions with MPO up to 200 ns. Together, these findings identified that out of 20 novel derivatives, 7di emerged as a dual MPO inhibitor and anti-inflammatory agent. These findings also highlight the branched heptacyclic architecture as a promising scaffold for advanced medicinal chemistry applications.