Design, synthesis, characterization, and biological evaluation of new diazole- benzamide derivatives as glucokinase activators with antihyperglycemic activity

Hamid, Ammar A.; Abdul-Rasheed, Omar F.; Mahdi, Monther F.; Atia, Abdul-Jabbar

doi:10.21608/ejchem.2022.100764.4682

Design, synthesis, characterization, and biological evaluation of new diazole- benzamide derivatives as glucokinase activators with antihyperglycemic activity

Document Type : Original Article

Authors

¹ Department of Pharmaceutical Chemistry, College of pharmacy, University of Kerbala, Iraq

² Department of Chemistry and Biochemistry, College of Medicine, Al-Nahrain University, Iraq

³ Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Iraq

⁴ Department of Chemistry, College of Science, Mustansiriyah University Iraq.

10.21608/ejchem.2022.100764.4682

Abstract

Background: Glucokinase (GK) is an essential enzyme that acts as an insulin sensor and is involved in glucose regulation. It is found in pancreatic β-cells and liver hepatocytes. As a result, GK might be a promising target for treating T2DM. GK activators are new antihyperglycemic drug candidates that work by activating the enzyme allosterically. Methodology: New benzamide nucleus derivatives were carefully developed, subjected to energy minimization, and then docked utilizing the Genetic Optimization of Ligand Docking method (GOLD). Following the in silico design and docking process, chemical syntheses utilizing a well-defined synthetic strategy culminated in the successful syntheses of these compounds, which were purified and characterized. A reliable animal model for T2DM was obtained by feeding mice with high fructose diet for 8 weeks. These mice were used then to study the hypoglycemic effect of the synthesized compounds by the application of OGTT. Finally an enzymatic assay was done to evaluate the activation of these compounds to the target enzyme. Results: The docking studies of the synthesized compounds (1c & 2c) revealed a complementary fit in the GK protein's allosteric binding site. Considering the PLP fitness, the hydrogen bonding and the hydrophobic interactions; compound 2c was superior to compound 1c. All the compounds were synthesized with a good yield. Characterization and identification of these compounds were done individually using FT-IR spectroscopy, 1H & 13C NMR and MS. The results of these analyses were in consistence with the proposed structures of the compounds. The animal model was successfully achieved, this was confirmed by the resultant impaired OGTT and the observation of the metabolic changes that occurred after fructose feeding period. In vivo biological evaluation using OGTT revealed a good glucose lowering activity of the synthesized compounds. These results were compatible with that obtained from in vivo enzymatic activity assay and in silico studies which showed that compound 2c has better activity than compound 1c. These new benzamide derivatives might be used as the starting hits for the establishment of safe, potent, and orally bioavailable GKAs for the treatment of T2DM.

Keywords

Main Subjects