Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives – Imidazoline Receptor Agonists

Abstract

Introduction

The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats.

Methods

The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances.

Results & Discussion

The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

Keywords:

• imidazoline receptors
• benzimidazole derivatives
• synthesis
• antihyperglycemic activity

Institutional Review Board Statement

The animals were cared for according to the international guidelines 33647-2015 (Principles of the Good Laboratory Practice, GLP), the international recommendations of the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes (The European Convention, 1986). The protocol of the experimental study was approved by the Ethics Committee of Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences (protocol № 4-2022 of 14.12.2022). License for the software system Yasara # 179465823.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.

Additional information

Funding

This research was funded by National Academy of Medical Sciences of Ukraine, grant number 0122U000375.