Design, Molecular Docking, Synthesis, Characterization and Preliminary Evaluation of Novel 1,3,4-Oxadiazole Derivatives as Cyclin-Dependent Kinase 2 Inhibitors

Abstract

Novel 1,3,4-oxadiazole derivatives were designed, synthesized by reaction of semicarbazide hydrochloride with thiophene-2-carbaldehyde to form semicarbazone that undergo iodine-mediated cyclization to form 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine which further reacted with different aldehydes to form Schiff base derivatives, and in-vitro tested for their cytotoxic activity. In a molecular docking study, these chemicals were docked with the crystal structure of the cyclin-dependent kinase 2 protein (PDB code 2R3J) to assess their binding affinity. The recently developed analogues were validated, confirmed, and characterized using spectroscopic elemental analysis (FT-IR, 1H-NMR, and 13C-NMR). Furthermore, these compounds underwent physicochemical, drug-like, and toxicological predictions. The molecular docking investigation shows that 1,3,4-oxadiazole derivatives bind strongly to the CDK-2 protein's active binding site. From the studied molecules, compounds 5a and 5d had the highest binding, with docking scores of -10.654 and -10.169 kcal/mol. The reference ligand binding score was -9.919 kcal/mol. As assessed by their anti-proliferative effects, compounds 5a and 5d showed promising cytotoxicity against colon cancer in Caco-2 cells. The compounds had IC50 values of 43.16 and 60.8 μM at 24 hours, respectively, compared to the standard flavopiridol (59.2 μM). The findings of the cytotoxicity investigation and molecular docking analysis of these final derivatives (5a-5g) demonstrated a strong correlation, indicating the importance of a comprehensive pharmacological study to comprehend the anti-cancer mechanisms of these newly synthesized compounds fully.

Keywords

• 1,3,4-Oxadiazole
• Colon Cancer
• Molecular Docking
• Schiff’s Bases