Substituted Bipyridine-Based Compounds: Synthesis, Enzyme Inhibition, Anticancer Activities and Molecular Docking Studies

Abstract

Background Substituted bipyridine-based compounds with diverse pharmacological activities like anticancer, anti-inflammatory, antimicrobial, antiviral, and antioxidant hold a significant scaffold in the pharmaceutical industry because of their biological activities. Objective These derivatives were synthesized and tested for their inhibitory and cytotoxicity activity against acetylcholinesterase (AChE), glutathione S-transferase (GST), and hepatocellular carcinoma (HepG2). Methods In AChE and GST inhibition measurement methods, a method based on quantitatively evaluating the inhibitory effect by measuring the enzyme's conversion of the substrate into a product and the resulting color change or absorbance of this product has been used. Results These bipyridine-based compounds were found to inhibit these enzymes with IC<inf>50</inf> values ranging from 1.99 to 3.15 μM for AChE and from 2.07 to 4.15 μM for GST. The bipyridine-based compounds were tested in a range of 12.5–100 µM concentrations against the HepG2 cell line. Among these derivatives studied, 15c was the most effective substance on HepG2 cells. Conclusion 15c was detected and found to be the best active bipyridine-based compound with an IC50 of 1.99 µM for AChE and 2.07 µM for GST, respectively. Also, 15a and 15d were good inhibitors for both enzymes. The time- and dose-dependent cytotoxicity determined supports bipyridine-based compounds’ potential as chemotherapeutic candidates for HepG2 cells. 15d and 15e derivatives possess good anticancer activity. Furthermore, the molecular docking results indicated that the bipyridine-based compounds predicted strong binding and stability at the active site of enzymes and the cancer line. The bipyridine-based compounds may enable the development of more selective and effective structures as enzyme inhibitors and anticancer drugs in the future. © 2026 The Authors.