Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2023)

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

  • Abdelrahman Hamdi,
  • Muhammad Yaseen,
  • Wafaa A. Ewes,
  • Mashooq Ahmad Bhat,
  • Noha I. Ziedan,
  • Hamed W. El-Shafey,
  • Ahmed A. B. Mohamed,
  • Mohamed R. Elnagar,
  • Abdullah Haikal,
  • Dina I. A. Othman,
  • Abdullah A. Elgazar,
  • Ahmed H. A. Abusabaa,
  • Kamal S. Abdelrahman,
  • Osama M. Soltan,
  • Mostafa M. Elbadawi

DOI
https://doi.org/10.1080/14756366.2023.2231170
Journal volume & issue
Vol. 38, no. 1

Abstract

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This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.

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