Design, Synthesis, molecular dynamic analysis, and In-Vivo anti-diabetic evaluation of novel hydrazine carboximidamide derivatives

• Published in: Results in Chemistry Vol. 11; p. 101791
• Main Authors: Fathi, Hannane, Naderi, Nima, Hashemi, Seyedali, Pourbaba, Yasaman, Garmabdari, Amir, Rezaee, Elham, Mahboubi-Rabbani, Mohammad, Abbas Tabatabai, Sayyed
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024; Elsevier
• Subjects: Antidiabetic; DPP-4; Hydrazine carboximidamide; Molecular Dynamic Analysis; DPP-4; Hydrazine carboximidamide; Molecular Dynamic Analysis; Antidiabetic
• ISSN: 2211-7156; 2211-7156
• DOI: 10.1016/j.rechem.2024.101791

[Display omitted] Diabetes is one of the most rapidly growing health problems globally, and researchers working hard to develop novel efficient therapies against it. In this regard, hydrazine carboximidamide has a great deal of attention owing to its diverse biological activities. Herein, a new series of N, N-disubstituted hydrazine carboximidamide derivatives was designed, synthesized, and assessed for their antidiabetic activity. Docking studies were performed to initially evaluate the binding of the designed compounds to the target enzyme. It was found that all of the pivotal ligand-enzyme interactions, including the interactions with Glu205/Glu206 aminoacids were observed in docking studies. The molecular dynamic analysis showed that the antidiabetic activity of the newly developed compounds may be implemented through the inhibition of dipeptidyl peptidase 4 (DPP-4), an important target that involves enhancing insulin release and suppressing glucagon discharge from the pancreas. The target molecules were synthesized practically and all the newly-developed chemical structures were confirmed via spectrophotometric methods, including IR, LC-MS, 1H NMR, and 13C NMR techniques. Finally, the in-vivo studies were carried out to confirm the results obtained from the docking and molecular dynamics studies. Compounds 6b and 6d demonstrated improved glucose tolerance through oral glucose tolerance tests in NMRI mice (at a dose of 10 mg/kg). Furthermore, prolonged administration of compounds 6b and 6d to diabetic Wistar rats for 14 days led to a noteworthy reduction in blood levels of glucose, akin to the effects observed with sitagliptin, a standard diabetes medication.