Axially Functionalized Silicon Phthalocyanines as Dual Cholinesterase Inhibitors: Synthesis, Biological Evaluation, DFT, and Molecular Docking Studies

In the present study, three axially substituted silicon phthalocyanine derivatives, namely H1-SiPc (5), H3-SiPc (6), and H7-SiPc (7), were synthesized via the axial functionalization of silicon phthalocyanine dichloride with benzo[h]quinolin-10-ol, 6-hydroxyflavanone, and N-(hydroxymethyl)phthalimide, respectively. The structures of the synthesized compounds were confirmed by FT-IR, 1H-NMR, MALDI-TOF-MS, and UV–Vis spectroscopic analyses. The cholinesterase inhibitory activities of the compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified Ellman method. All derivatives exhibited significant dual inhibitory activity toward both enzymes in the low micromolar concentration range. Among the investigated compounds, H7-SiPc (7) displayed the strongest inhibitory activity, with IC50 values of 3.78 ± 0.3 μM and 1.93 ± 0.3 μM against AChE and BChE, respectively. To gain deeper insight into their electronic properties and biological behavior, density functional theory (DFT) calculations were performed using B3LYP, HF, and M06-2X methods with the 6–31++G(d,p) basis set. The calculated frontier molecular orbital energies, global reactivity descriptors, and dipole moments demonstrated that axial substituent modification significantly affects the electronic characteristics of the silicon phthalocyanine framework. Furthermore, molecular docking studies against selected protein targets (4M0E, 5NN0, 1OCE, and 6R6V) revealed favorable ligand–protein interactions, with H3-SiPc (6) exhibiting the strongest binding affinities for most of the investigated receptors. The combined experimental and computational findings highlight the importance of axial functionalization in modulating the physicochemical and biological properties of silicon phthalocyanines and suggest that these derivatives represent promising candidates for the development of multifunctional anti-Alzheimer agents.