Synthesis of novel thiazole derivatives containing 3-methylthiophene carbaldehyde as potent anti α-glucosidase agents: In vitro evaluation, molecular docking, dynamics, MM-GBSA, and DFT studies

Thiazole derivatives bearing thiophene carbaldehyde have been successfully prepared by refluxing 3-methylthiophene carbaldehyde with thiosemicarbazide in absolute ethanol followed by treating the obtained product with different phenacyl bromide to get thiazole products in better yields. These derivatives were confirmed using H-1-, C-13 NMR, and EI-MS spectrometry techniques and finally subjected for their alpha-glucosidase inhibitory potential. Two compounds in the series including 2 g (IC50 = 9.00 +/- 0.57 mu M) and 2b (IC50 = 13.50 +/- 0.20 mu M) were found as the most potent alpha-glucosidase inhibitors better than the standard acarbose. Furthermore, the remaining five compounds attributed significantly to less activity. The studied molecules were calculated on the 6-31++g(d,p) basis set at B3LYP, HF, M062X levels with the help of the Gaussian package program, and their chemical activities were compared. Following that, the molecules' interactions with different alpha-glucosidase proteins (PDB IDs: 1R47 and 1UAS) were investigated, and their activities were contrasted. The binding free energy of the molecule with the best docking score is computed using MM/GBSA techniques. The comparative molecular dynamics simulations of the 2g-1UAS and 2g-1R47 complexes highlight the intricate balance of forces that govern biomolecular interactions. The findings suggest that while the 2g-1UAS complex forms more stable interactions, as indicated by lower RMSD values, the 2g-1R47 complex maintains its structural integrity through strong hydrogen bonds. Overall, the equilibrium conformations achieved by both complexes suggest they are well-suited for their roles in physiological environments.