In vitro and in silico α-glucosidase Inhibition Studies of Two Water-soluble Copper(II) and Manganese(III) Phthalocyanines

Abstract

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by impaired insulin activity and hyperglycemia, which often leads to severe complications. Current therapeutic agents such as acarbose exert their effects through α-glucosidase inhibition; however, their clinical utility is often restricted due to gastrointestinal side effects, highlighting the urgent need for safer and more effective alternatives. Phthalocyanines, known for their structural stability and versatile biological activities, represent promising candidates in this field. In this study, two previously synthesized water-soluble peripheral tetra-substituted metallophthalocyanine complexes, copper(II) phthalocyanine (CuPc) and manganese(III) phthalocyanine (MnPc), were evaluated for their α-glucosidase inhibitory potential using both in vitro and in silico approaches. The IC50 values of CuPc (14.90 ± 0.59 µM) and MnPc (12.91 ± 0.29 µM) were lower than that of acarbose (237.24 ± 1.80 µM), indicating stronger inhibitory effect in vitro. Kinetic studies revealed that MnPc displayed competitive inhibition with a Ki value of 1.88 µM. Molecular docking simulations further supported these findings, with binding affinities of −9.8 kcal/mol for CuPc and −9.3 kcal/mol for MnPc against α-glucosidase (PDB ID: 3WY2). Structural analyses showed that CuPc binding was dominated by hydrophobic and π-interactions, while MnPc formed an extensive hydrogen-bonding network in addition to hydrophobic contacts. These combined interactions may contribute to their observed binding affinity and inhibitory activity. Overall, the results indicate that CuPc and MnPc are potent in vitro α-glucosidase inhibitors and provide a basis for further investigation of these compounds as potential antidiabetic agents. However, additional in vivo efficacy, toxicity, and pharmacokinetic studies are required to further evaluate their therapeutic potential.