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

• Published in: Journal of molecular structure 2025-02, Vol.1321, p.140070, Article 140070
• Main Authors: Ullah, Najeeb, Alam, Aftab, Zainab, Tüzün, Burak, Rehman, Najeeb Ur, Ayaz, Muhammad, Elhenawy, Ahmed A., Khan, Ajmal, Rahman, Sajjad Ur, Ali, Mumtaz, Latif, Abdul, Al-Harrasi, Ahmed, Ahmad, Manzoor
• Format: Article
• Language: English
• Subjects: 5-methylthiophene carbaldehyde; Benzothiazole; Dynamics; MM-GBSA and DFT; Molecular Docking; α-glucosidase inhibition
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140070

•Synthesis novel thiazole derivatives bearing 3-methylthiophene carbaldehyde.•Structural elucidation through modern spectroscopic techniques such as, EI-MS, and 1H NMR.•Evaluation of the synthesized compounds for their in vitro α-glucosidase inhibitory activity.•Molecular docking and TD-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 1H-, 13C NMR, and EI-MS spectrometry techniques and finally subjected for their α-glucosidase inhibitory potential. Two compounds in the series including 2 g (IC50 = 9.00 ± 0.57 µM) and 2b (IC50 = 13.50 ± 0.20 µM) were found as the most potent α-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 α-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.