Synthesis, single crystal XRD, in-vitro, and in-silico studies of polysubstituted tetrahydropyridine as α-amylase inhibitor

• Published in: Journal of molecular structure 2024-06, Vol.1305, p.137770, Article 137770
• Main Authors: Khan, Obaid ur Rehman, Latif, Saba, Khan, Bilal Ahmad, Yousaf, Sammer, Ashfaq, Muhammad, Munawar, Khurram Shahzad, Rashid, Zahid, Sayed, Shaban R.M., Sidhom, Peter A., Hegazy, Mohamed-Elamir F., Ibrahim, Mahmoud A.A.
• Format: Article
• Language: English
• Subjects: Hirshfeld surface analysis; Molecular docking; Tetrahydropyridine; XRD analysis; α-amylase enzyme
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.137770

•Densely substituted tetrahydropyridines were synthesized as potential α-amylase inhibitors.•The obtained compounds were thoroughly characterized using various spectroscopic techniques.•PMAAA demonstrated promising activities against α-amylase with an IC50 value of 40.54±5.0 mg/mL.•Molecular modeling studies were executed to predict the binding mode of PMAAA against α-amylase. The inhibition of α-amylase, an enzyme responsible for the breakdown of starch, has gained opulent attention as a therapeutic target for managing conditions such as diabetes and obesity. In that spirit, the synthesis of densely substituted tetrahydropyridines (PMAAA - PMAAH) as a potential α-amylase inhibitor was herein undertaken. The obtained compounds were thoroughly characterized utilizing 13C-NMR, 1H-NMR, and FT-IR spectroscopic techniques, confirming their structural integrity and purity. Single crystal XRD analysis was also performed to determine the crystal structure of the PMAAA, providing valuable insights into its molecular arrangement and intermolecular interactions. Furthermore, in-silico studies were employed to gain a deeper understanding of the binding interactions between the PMAAA and the active site of α-amylase. The supramolecular assembly was mainly stabilized by H-bonding and explored by Hirshfeld surface analysis. Void analysis predicted the mechanical response of the crystal. α-Amylase inhibition study has shown that PMAAA demonstrated an IC50 value of 40.54±5.0 mg/mL, compared to 8.80±0.21 mg/mL for acarbose as a reference inhibitor. To further explore the interaction of PMAAA with α-amylase, a molecular docking simulation was performed. The docking analysis showed that there is a strong interaction between the PMAAA ligand and α-amylase, with a binding score of −8.4 kcal/mol. These findings pave the way for further research and potential applications in the management of conditions related to α-amylase dysregulation, such as diabetes and obesity.