Structure–Activity Relationships of Morpholine-Modified Silicon(IV) Phthalocyanines as Potential Antidiabetic Agents

Abstract

Type 2 diabetes mellitus (DM) is a chronic metabolic disorder with a rapidly increasing global prevalence, highlighting the need for safer and more effective therapeutic strategies. In this study, a series of axially disubstituted silicon(IV) phthalocyanines bearing morpholine functional groups and their water-soluble derivatives were synthesized, structurally characterized, and evaluated for their antidiabetic potential. The synthesized compounds were characterized by FT-IR, 1H and 13C NMR, UV–Vis spectroscopy, and mass spectrometry. The in vitro antidiabetic activity of the compounds was evaluated through α-glycosidase and α-amylase inhibition assays. The non-ionic silicon(IV) phthalocyanine derivatives MT-C3-H-Si and MT-C3-D-Si exhibited strong α-glucosidase inhibitory activity with IC50 values of 16.02 ± 0.94 μM and 44.14 ± 4.06 μM, respectively, showing higher potency than the standard inhibitor acarbose (IC50 = 60.51 ± 4.66 μM). In contrast, the water-soluble derivatives MT-C3-H-SiQ and MT-C3-D-SiQ displayed lower inhibitory activity (IC50 = 68.80 ± 5.12 μM and >100 μM, respectively), indicating that increased hydrophilicity does not necessarily enhance enzyme inhibition. All compounds exhibited weak α-amylase inhibition (IC50 >100 μM) compared with acarbose (IC50 = 25.29 ± 3.50 μM). Kinetic studies revealed that MT-C3-H-Si and MT-C3-D-Si inhibit α-glycosidase via a non-competitive mechanism, with Ki values of 9.45 ± 1.45 μM and 29.06 ± 5.16 μM, respectively. This characterized by decreased Vmax values without significant changes in Km, suggesting interaction with allosteric regions of the enzyme. Overall, these findings highlight axially disubstituted silicon(IV) phthalocyanines as promising molecular scaffolds and contribute valuable insight into the limited literature on their antidiabetic enzyme inhibition properties.