Biological, toxicological and molecular docking evaluations of isoxazoline-thiazolidine-2,4-dione analogues as new class of anti-hyperglycemic agents

Abstract

In this work, three isoxazoline-thiazolidine-2,4-dione derivatives were synthesized and characterized by FT-IR, ¹H-NMR, ¹³C-NMR and ESI-MS spectrometry. All compounds have been investigated for their α-amylase and α-glucosidase inhibitory activities. In vitro enzymatic evaluation revealed that all compounds were inhibitory potent against α-glucosidase with IC₅₀ values varied from 40.67 ± 1.81 to 92.54 ± 0.43 µM, and α-amylase with IC₅₀ in the range of 07.01 ± 0.02 to 75.10 ± 1.06 µM. One of the tested compounds were found to be more potent inhibitor compared to other compounds and standard drug Acarbose (IC_{50 glucosidase}= 97.12 ± 0.35 µM and IC_{50 amylase}= 2.97 ± 0.01 μM). All compounds were then evaluated for their acute toxicity in vivo and shown their safety at a high dose with LD > 2000mg/kg BW. A cell-based toxicity evaluation was performed to determine the safety of compounds on liver cells, using the MTT assay against HepG2 cells, and the results shown that all compounds have non-toxic impact against cell viability and proliferation compared to reference drug (Pioglitazone). Furthermore, the molecular homology analysis, SAR and the molecular binding properties of compound with the active site of α-amylase and α-glucosidase were confirmed through computational analysis. This study has identified the inhibitory potential of a new class of synthesized isoxazoline-thiazolidine-2,4-dione derivatives in controlling both hyperglycemia and type 2 diabetes mellitus without any hepatic toxicity.

Communicated by Ramaswamy H. Sarma

Keywords:

• Thiazolidine-2,4-dione
• isoxazoline
• antihyperglycemic potential
• α-amylase inhibition
• α-glucosidase inhibition
• SAR
• toxicity analysis

Acknowledgement

Authors thank all collaborators for their constant support and encouragement.

Disclosure statement

The authors declare that they have no competing financial interests that could have appeared to influence the work reported in this paper.