Potent Multi‐Target Inhibition of Cholinesterases and Carbonic Anhydrases by Iridium(III)–Phenanthroline Derivatives: Integrated Structure–Activity Relationship, Molecular Docking and Anticancer Cell Culture Studies

ABSTRACT In this study, a series of novel iridium(III) complexes incorporating 2‐phenylimidazo[4,5‐f][1,10]phenanthroline ligands with different substituents (methyl ( 1a ), isopropyl ( 2a ), methoxy ( 3a ), phenyl ( 4a )) were evaluated for their in vitro inhibitory activities against anticholinesterase (acetylcholinesterase [AChE], butyrylcholinesterase [BChE]) and carbonic anhydrase [hCA I] and [hCA II]) enzymes. Among the tested compounds, 2a demonstrated exceptional potency with IC 50 values of 66.5 ± 9.06 nM for AChE and 26.45 ± 5.00 nM for BChE, significantly outperforming tacrine. Compound 4a also exhibited strong inhibition of hCA I (IC 50 = 33.0 ± 7.09 nM) and hCA II (IC 50 = 41.79 ± 8.09 nM), surpassing the reference drug acetazolamide. Molecular docking studies revealed that compound 4a exhibited the strongest binding affinity with BChE (PDB: 4BDS) at ‐12.06 kcal/mol, while compound 2a showed strong binding to hCA II (PDB: 3HS4) at ‐8.768 kcal/mol. Molecular dynamics simulations over 150 ns confirmed the structural stability of the protein‐ligand complexes. Cell viability assays showed that compounds 1a–4a decreased PC3 prostate cancer cell viability in a concentration‐dependent manner, with IC 50 values of 10.09, 3.95, 11.39, and 4.51 µM, respectively. This comprehensive study highlights iridium(III) complexes as multitarget therapeutic agents with potent anticholinesterase and carbonic anhydrase inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders.