ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Synthesis and biological evaluation of 2-(2-methyl-1H-pyrrol-3-yl)-2-oxo-N-(pyridine-3-yl) acetamide derivatives: in vitro α-glucosidase inhibition, and kinetic and molecular docking study

Tadesse Bekele Tafesse, Ebrahim Saeedian Moghadam, Mohammed Hussen Bule, Neda Abadian, Mohammad Abdollahi, Mohammad Ali Faramarzi, and Mohsen Amini

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences-International Campus (IC-TUMS), Tehran, Iran

E-mail: faramarz@tums.ac.ir

Received: 31 March 2019  Accepted: 12 November 2019

Abstract:

One of the therapeutic approaches in the management of type 2 diabetes is delaying the glucose absorption through α-glucosidase enzyme inhibition, which can reduce the occurrence of postprandial hyperglycemia. Based on this thought, a series of novel chloro-substituted 2-(2-methyl-1-phenyl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3-yl) acetamide derivatives 5a–i were synthesized and their α-glucosidase inhibitory activities were evaluated. All the synthesized compounds have shown moderate to excellent in vitro α-glucosidase inhibitory activity with IC₅₀ values in the range of 111–673 µM) as compared to acarbose, the standard drug (750 ± 9 µM). Compound 5e (111 ± 12 µM), among the series, was the most potent inhibitor of α-glucosidase in a competitive mode of action based on the kinetic study. The molecular docking study of compounds 5e and 5a revealed that they have a lower free binding energy (− 4.27 kcal/mol and − 3.17 kcal/mol, respectively) than acarbose (− 2.47 kcal/mol), which indicates that the target compound binds more easily to the enzyme than acarbose does. The outcomes from the molecular docking studies supported the results obtained from the in vitro assay. In conclusion, the overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage postprandial hyperglycemia incidence.

Keywords: α-Glucosidase activity; Docking; Kinetic study; Synthesis; Pyrrole

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-019-00999-0

Chemical Papers 74 (5) 1583–1596 (2020)