Tailored pyrrole-based imidazothiazole scaffolds: Synthetic elaboration, enzyme kinetic profiling and DFT-guided...

The current research study highlights the successful biological evaluation of novel imidazo-thiadiazole based pyrrole derivatives, with the aim of targeting diabetes mellitus through alpha-amylase and alpha-glucosidase inhibition. These compounds exhibited promising anti-diabetic activity, notably compound 8 emerged as a leading candidate (3.50 ± 0.20, and 4.10 ± 0.10 µM) which outperformed the potential of acarbose (6.20 ± 0.10 and 6.70 ± 0.20 µM), a reference drug. The enhanced biological potential of compound 8 is likely due to incorporation of hydroxyl substituents, which may strengthen its binding affinity and selectivity towards the targeted enzymes. Molecular docking revealed stable interactions with key amino acids residues of targeted enzymes, providing mechanistic basis for its potent inhibitory activity. To further established their therapeutic relevance, enzyme kinetic study was conducted which confirmed their mode of inhibition while ADMET analysis indicated favorable pharmacokinetics and safety profiles. Moreover, pharmacophore modeling and molecular dynamics simulations reinforced the stability and binding efficiency of lead compounds under dynamic biological conditions. All the experimental results and in silico validations demonstrate that potent compounds possess significant anti-diabetic activity profile. Their ability to outperform an existing diabetes mellitus inhibitor and maintaining a favorable safety profile suggest that these compounds have potential to be further used in drug development and optimization against Diabetes Mellitus.