Water-soluble non-peripheral quinoline-substituted Co(II) and Cu(II) phthalocyanines as promising multi-target enzyme inhibitors: synthesis, enzyme kinetics, and molecular docking studies

Abstract

New non-peripherally quinoline-substituted cobalt(II) and copper(II) phthalocyanines and their quaternized water-soluble derivatives were synthesized, characterized, and investigated as multi-target enzyme inhibitors. The synthesized compounds were structurally confirmed by FT-IR, UV–Vis, NMR, ESI-MS, and MALDI-TOF MS analyses. The water-soluble derivatives, n-8K-C3-CuQ and n-8K-C3-CoQ, were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and α-glucosidase. Both compounds showed stronger AChE inhibition than galantamine, with IC₅₀ values of 1.65 ± 0.58 µM for n-8K-C3-CuQ and 1.60 ± 0.94 µM for n-8K-C3-CoQ. In BuChE inhibition, n-8K-C3-CoQ exhibited the highest activity with an IC₅₀ value of 4.71 ± 1.96 µM, markedly superior to galantamine. Moreover, both derivatives displayed pronounced α-glucosidase inhibition, with IC₅₀ values of 1.14 ± 0.85 and 1.36 ± 0.49 µM for n-8K-C3-CuQ and n-8K-C3-CoQ, respectively, compared with acarbose. Enzyme kinetic studies revealed enzyme- and metal-dependent inhibition mechanisms, including competitive, mixed-type, and non-competitive inhibition modes. Molecular docking analyses supported the experimental findings, with favorable binding scores toward AChE, BuChE, and α-glucosidase, reaching -9.0 kcal/mol. Overall, these results suggest that water-soluble quinoline-functionalized metallophthalocyanines may represent promising scaffolds for the development of multi-target cholinesterase and α-glucosidase inhibitors. However, further cytotoxicity, selectivity, and in vivo studies are required before their therapeutic potential can be fully established.