Celebrex derivatives: Synthesis, α-glucosidase inhibition, crystal structures and molecular docking studies

Abstract

Celebrex (1), commonly used as an anti-inflammatory drug, was functionalized (compounds 2-9) to identify new α-glucosidase inhibitors. Initially, all the synthesized derivatives were evaluated for anti-inflammatory activity but none was found to be active. Subsequently a random biological screening was carried out. Interestingly many of them were found to be potent α-glucosidase inhibitors in vitro. All the structures of synthesized derivatives were deduced through ¹H NMR, FAB-MS, HR-MS, FT-IR analysis. The single-crystal X-ray structures of compounds 1, and 5 further confirmed the assigned structures. Compounds exhibited a potent α-glucosidase inhibitory activity (IC₅₀ = 92.32 ± 1.530-445.20 ± 1.04 µM) against tested standard acarbose (IC₅₀ = 875.75 ± 2.08 µM), except compounds 2 and 4, which appeared as inactive. Among them, compound 9 (IC₅₀ = 92.32 ± 1.530 µM) was the most potent inhibitor of α-glucosidase enzyme. Molecular docking studies revealed that compounds 6, and 9 interacted with the key amino acid residues of α-glucosidase via H-bonding, and π-π stacking interactions. α-Glucosidase is a key target for the anti-diabetic drug development, and its inhibitors are known to exert anti hyperglycemic effect and help in lowering of post-prandial blood glucose levels.

Keywords: Celebrex; Crystal structure; Diabetes; Heterocyclic; Pyrazole; α-Glucosidase.