A manganese-salen complex as dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

• Published in: International journal of biological macromolecules 2018-12, Vol.120 (Pt A), p.1232-1239
• Main Authors: Zhu, Ming-rong, Zhou, Jie, Jin, Yi, Gao, Li-Hui, Li, Ling, Yang, Jun-Ru, Lu, Chun-Mei, Zhao, Qi Hua, Xie, Ming-jin
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - drug effects; Coordination Complexes - administration & dosage; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - pathology; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Enzyme inhibitors; Ethylenediamines - administration & dosage; Ethylenediamines - chemical synthesis; Ethylenediamines - chemistry; Glucose Tolerance Test; Humans; Manganese(II); Mice; Mice, Inbred NOD; Molecular docking; Molecular Docking Simulation; Organometallic Compounds - administration & dosage; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Schiff base complex; Schiff Bases - chemistry
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2018.08.089

A manganese Schiff base complex with N,N′-1,2-phenylenediamine-bis(salicyladimine) was synthesized and characterized by X-ray crystallography. This complex was administered intragastrically to alloxan-diabetic mice 3 weeks. In vivo tests showed that the complex significantly lowered serum glucose levels in alloxan-diabetic mice at doses of 77 mg V kg−1. Meanwhile, this complex was investigated as dipeptidyl peptidase IV (DPP-IV) inhibitor for the treatment of type 2 diabetes. The compound exhibit moderate inhibition against DPP-IV and possessed an IC50 value of 30 μM. Lineweaver–Burk transformation of the inhibition kinetics data demonstrated that it was a noncompetitive inhibitor of DPP-IV and Ki value was 136.3 μM. Moreover, molecular modeling studies suggested that the complex could fit well within the active-site cleft of DPP-IV. An acute toxicity study showed that animals treated intragastically with complex 1 at a dose of 5.0 g/kg did not show any significantly abnormal signs. These preliminary results suggest that the manganese Schiff base complex can induce a hypoglycemic effect in alloxan-diabetic mice.