Work

Design, synthesis, and evaluation of some benzimidazole analogs as AMPK agonists

Year: 2024

Type: article

Abstract: AMP-activated protein kinase is a crucial regulator of cellular metabolism with potential therapeutic implications in various diseases. In this study, the benzimidazole scaffold was chosen for investigation with EX-229 as the lead compound. Modifications were made to the terminal carboxyl group, and the methylindole moiety was replaced with phenylpyrrolidinone to synthesize and assess the AMP-activated protein kinase-activating properties of 13 benzimidazole derivatives. In vitro studies have shown that most of the synthesized compounds have significant excitatory effects on AMP-activated protein kinase. Particularly, A11 demonstrated the most potent activity with an EC 50 value of 39 nM. Combining activity data and molecular docking analysis revealed the necessity of end-molecule hydrogen bond donors for LYS29, and the importance of an appropriate torsion angle at the pyrrolidinone position to facilitate the formation of a crucial hydrogen bond with LYS31. These discoveries offer preliminary insights into the interaction of small-molecule drugs with the AMP-activated protein kinase protein and establish a foundation for the future development of AMP-activated protein kinase activators guided by structure–activity relationships.

Source: Journal of Chemical Research

DOI: 10.1177/17475198241290882

Authors: Runtao Tian, Jiajia Zhang, Yujia Zhang, Huaiwei Ding

Institution: Shenyang Pharmaceutical University

Language: English

Topic: Synthesis and biological activity

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,100