2. Academic Validation
  3. Synthesis, in vitro and in vivo evaluation, and computational modeling analysis of thioxothiazolidine derivatives as highly potent and selective α-amylase inhibitors

Synthesis, in vitro and in vivo evaluation, and computational modeling analysis of thioxothiazolidine derivatives as highly potent and selective α-amylase inhibitors

  • Eur J Med Chem. 2025 Jul 5:291:117584. doi: 10.1016/j.ejmech.2025.117584.
Anil Ravi 1,  Sumera Zaib 2,  Shabab Zahra 3,  Imtiaz Khan 4,  Hafiz Saqib Ali 5,  Mohammed I El-Gamal 6,  Hanan S Anbar 7
Affiliations

Affiliations

  • 1 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 2 Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore, 54590, Pakistan. Electronic address: [email protected].
  • 3 Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore, 54590, Pakistan.
  • 4 Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom. Electronic address: [email protected].
  • 5 Chemistry Research Laboratory, Department of Chemistry and the INEOS Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom.
  • 6 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 7 Department of Pharmaceutical Sciences, Dubai Pharmacy College for Girls, Dubai Medical University, Dubai, 19099, United Arab Emirates. Electronic address: [email protected].
PMID: 40220676 DOI: 10.1016/j.ejmech.2025.117584
Abstract

Diabetes mellitus is not only a critical health concern in this era but also a major cause of damage to Other organs such as eyes, nerves, kidneys, hearts and liver. Inhibiting α-amylase enzyme is considered as one of the key strategies for controlling chronic hyperglycemia. Therefore, the current work focuses on design and discovery of a series of thioxothiazolidine derivatives (5a-u and 6a-g) as selective α-amylase inhibitors. The target compounds were synthesized using the Knoevenagel condensation approach and evaluated for their α-amylase and α-glucosidase inhibitory activities. The in vitro assay results demonstrated that the tested thioxothiazolidine derivatives possess significantly high potency than the standard drug acarbose against α-amylase but were inactive against α-glucosidase. Among them, compound 5r exhibited remarkable inhibitory potential depicting an IC50 value of 0.71 ± 0.01 μM, significantly outperforming acarbose against α-amylase. In vivo results further demonstrated that the treatment of diabetic rats with compound 5r led to a significant reduction in blood glucose level, indicating its effectiveness in managing hyperglycemia. Biochemical profiling of the treated rats revealed favorable outcomes, including improved urea, creatinine, ALT, AST, ALP, and HbA1C values. Furthermore, in vivo testing in diabetic rats also demonstrated that treatment with compound 5r caused significant histopathological improvements in the kidney, liver and pancreas compared to acarbose. The Lineweaver-Burk plot analysis indicated that compound 5r inhibits α-amylase through a mixed type of inhibition mechanism. Furthermore, molecular docking and dynamics simulations confirmed the in vitro findings while pharmacokinetic properties suggested compound 5r as a favorable drug candidate for the treatment of diabetic complications.

Keywords

Diabetes management; Histopathological analysis; Thioxothiazolidine; α-Amylase inhibition.

Figures
Products