Unveiling anti-diabetic potential of new thiazole-sulfonamide derivatives: Design, synthesis, in vitro bio-evaluation targeting DPP-4, α-glucosidase, and α-amylase with in-silico ADMET and docking simulation

Jul 27, 2024Bioorganic chemistry

New thiazole-sulfonamide compounds designed and tested for anti-diabetic effects by targeting key blood sugar enzymes with computer simulations and lab tests

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Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors based on new thiazole derivatives demonstrated binding affinities ranging from -6.86 to -5.36 kcal/mol.

The designed thiazole derivatives exhibited good to moderate activity against DPP-4, with some showing greater potency than Sitagliptin.
In vitro assays indicated inhibitory percentages for the new compounds ranging from 40.66 to 75.62%, compared to Sitagliptin's 63.14%.
Compounds 10 and 11 displayed strong inhibitory concentrations (IC50) of 2.75 ± 0.27 µM and 2.51 ± 0.27 µM, respectively, outperforming Sitagliptin.
Compound 10 showed significant activity against α-glucosidase with an IC50 of 3.02 ± 0.23 µM, while compound 11 was most effective against α-amylase with an IC50 of 2.91 ± 0.23 µM.
The structure-activity relationship (SAR) analysis emphasized the role of hydrophobic substituents in enhancing the activity of the thiazole scaffold.

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Diabetes mellitus type 2 (T2DM) can be managed by targeting dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down and deactivates peptides such as GIP and GLP-1. In this context, a new series of 2-(2-substituted hydrazineyl)thiazole derivatives 4, 5, 6, 8, 10, and 11 conjugated with the 2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzylidene fragment were designed and synthesized. The virtual screening of the designed derivatives inside DPP-4 demonstrated good to moderate activity, with binding affinity ranging from -6.86 to -5.36 kcal/mol compared to Sitagliptin (S=-5.58 kcal/mol). These results encourage us to evaluate DPP-4 using in-vitro fluorescence-based assay. The in-vitro results exhibited inhibitory percentage (IP) values ranging from 40.66 to 75.62 % in comparison to Sitagliptin (IP=63.14 %) at 100 µM. Subsequently, the ICvalues were determined, and the 5-aryl thiazole derivatives 10 and 11 revealed strong potent ICvalues 2.75 ± 0.27 and 2.51 ± 0.27 µM, respectively, compared to Sitagliptin (3.32 ± 0.22 µM). The SAR study exhibited the importance of the substituents on the thiazole scaffold, especially with the hydrophobic fragment at C5 of the thiazole, which has a role in the activity. Compounds 10 and 11 were further assessed toward α-glucosidase and α-amylase enzymes and give promising results. Compound 10 showed good activity against α-glucosidase with ICvalue of 3.02 ± 0.23 µM compared to Acarbose 3.05 ± 0.22 µM and (11 = 3.34 ± 0.10 µM). On the other hand, for α-amylase, compound 11 was found to be most effective with ICvalue of 2.91 ± 0.23 µM compared to compound 10 = 3.30 ± 0.16 µM and Acarbose (2.99 ± 0.21 µM) indicating that these derivatives could reduce glucose by more than one target. The most active derivatives 10 and 11 attracted great interest as candidates for oral bioavailability and safe toxicity profiles compared to positive controls. The in-silico docking simulation was performed to understand the binding interactions inside the DPP-4, α-glucosidase, and α-amylase pockets, and it was found to be promising antidiabetic agents through a number of interactions. 50 50 50 50

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Unveiling anti-diabetic potential of new thiazole-sulfonamide derivatives: Design, synthesis, in vitro bio-evaluation targeting DPP-4, α-glucosidase, and α-amylase with in-silico ADMET and docking simulation

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