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

Apr 12, 2025European journal of medicinal chemistry

Design and testing of thioxothiazolidine compounds as strong and selective blockers of the enzyme alpha-amylase

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Abstract

Compound 5r demonstrated an IC value of 0.71 ± 0.01 μM as a potent inhibitor of α-amylase.

Thioxothiazolidine derivatives were developed as selective inhibitors of α-amylase.
In vitro assays showed that these derivatives had a significantly higher potency against α-amylase compared to the standard drug acarbose.
Compound 5r not only reduced blood glucose levels in diabetic rats, but also improved various biochemical markers including urea, creatinine, and HbA1C.
Histopathological analysis indicated that compound 5r improved kidney, liver, and pancreas health in comparison to treatment with acarbose.
Compound 5r inhibits α-amylase through a mixed type of inhibition mechanism, as confirmed by Lineweaver-Burk plot analysis.
Molecular docking and dynamics simulations supported the in vitro findings, suggesting favorable pharmacokinetic properties for compound 5r.

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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 ICvalue 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. 50

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

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