Quinoline and Phthalimide Substituted Silicon Phthalocyanines as Multi-Target Inhibitors of Cholinesterases and Carbonic Anhydrases.

Two novel axially substituted silicon phthalocyanines bearing 5,7-dichloro-8-hydroxy-2-methylquinoline (1a) and N-(hydroxymethyl)phthalimide (2a) moieties were synthesized and characterized by UV-Vis, FT-IR, 1H NMR, and mass spectrometry techniques. The biological potential of the synthesized compounds was evaluated through in vitro inhibition studies against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoenzymes I and II (hCA I and hCA II). IC50 values were determined as 91.28 ± 25.21, 43.31 ± 20.35, 8.50 ± 2.80 and 23.35 ± 12.98 µM, for compound 1a, and 2.78 ± 1.05, 4.88 ± 1.50, 0.94 ± 1.06 and 4.15 ± 3.01 µM for compound 2a against AChE, BChE, hCA I, and hCA II enzymes respectively. Compound 2a exhibited remarkable inhibitory activity. Molecular docking results supported the experimental findings, indicating that compound 2a exhibited significantly higher inhibitory potency than compound 1a. Structure-activity relationship analysis demonstrated that compound 2a exhibits improved enzyme inhibition. The combined experimental and computational findings showed that compound 2a is a promising multifunctional enzyme inhibitor. Compound 2a exhibited remarkable inhibitory activity across all targets. Molecular docking supported the experimental findings, with compound 2a showing more favorable Vinardo binding affinities (-8.11, -3.94, -7.39, and -7.15 kcal/mol against AChE, BChE, hCA I, and hCA II, respectively) than compound 1a, primarily through additional hydrogen-bonding interactions provided by its phthalimide groups. The docking protocol was validated by redocking the co-crystallized ligands, which reproduced the crystallographic poses with RMSD values below 2.0 Å for all targets. DFT calculations revealed narrow HOMO-LUMO energy gaps (0.666 eV for 1a and 0.881 eV for 2a), consistent with the high reactivity of the phthalocyanine core, while in silico ADMET analysis indicated favorable toxicity profiles for both compounds. The combined experimental and computational findings identify compound 2a as a promising multifunctional enzyme inhibitor.