Fecha de publicación: -- Fuente: "milk OR dairy products" Arch Pharm (Weinheim). 2026 Sep;359(9):e70346. doi: 10.1002/ardp.70346.ABSTRACTLactoperoxidase (LPO, EC 1.11.1.7), a heme metalloenzyme central to innate antimicrobial defence and implicated in mammary carcinogenesis, remains an underexplored target for metal-based inhibitors. We evaluated six cyclometalated iridium(III) complexes bearing 2,2'-bipyridine-4,4'-dicarboxamide ancillary ligands with varied N-substituents as LPO inhibitors. Kinetic analysis using LPO purified from bovine milk revealed nanomolar inhibition (IC50 = 0.64-3.12 nM; Kᵢ = 0.05 ± 0.01-5.36 ± 1.88 nM), representing an approximately 107-fold potency advantage over the benchmark sulfonamide acetazolamide. Lineweaver-Burk analysis showed substituent-dependent inhibition: complexes 1, 2, and 4 were competitive, whereas 3, 5, and 6 were non-competitive, indicating that peripheral steric features influence the inhibition mechanism. Density functional theory calculations showed smaller HOMO-LUMO gaps and higher electrophilicity indices than acetazolamide, although no single descriptor predicted activity within the series. Molecular docking supported binding within the distal heme cavity, with representative interactions including π-π stacking and hydrogen bonding involving Gln-105 and His-109. All complexes reduced MDA-MB-231 cell viability; among those with reliably determined IC50 values, complex 4 showed the greatest cytotoxicity (IC50 = 18.28 µM). These findings identify amide-linked Ir(III) complexes as highly potent LPO inhibitors with substituent-dependent inhibition modes.PMID:42784743 | DOI:10.1002/ardp.70346