Structure-guided design and development of vanillin-triazole conjugates as potential MARK4 inhibitors targeting hepatocellular carcinoma

Microtubule affinity-regulating kinase 4 (MARK4) is a potential therapeutic target for cancer therapy, as it plays a crucial role in cell division and metastasis. Vanillin is an essential ingredient of vanilla bean extract and has several pharmacological activities, including high inhibitory potential for MARK4. This study aimed to synthesize vanillin-triazole derivatives to develop MARK4-specific inhibitors. We employed experimental and computational approaches to investigate the potentials of synthesized vanillin-triazoles (5a–q) for inhibiting MARK4 activity and subsequent growth of hepatocellular carcinoma (HCC) cells (C3A/HepG2 and SNU-475). In addition, molecular docking and MD simulation studies suggest that vanillin-triazoles bind strongly with the active site residues of MARK4 and are stabilized by numerous non-covalent interactions. Among all 5a, 5g, 5h, and 5j showed an appreciable enzyme inhibition profile and strong binding affinities with MARK4 in the sub-micromolar range. Moreover the compound 5g suppresses the cell proliferation and migration potential of C3A and SNU-475 cells and strongly induces apoptosis. The present study suggests that vanillin-triazole (5g) has high inhibitory activity towards MARK4 and could be utilized for developing MARK4-based anticancer therapies.