Copper‐Catalyzed Synthesis and Anti‐Pancreatic Cancer Evaluation of Novel Pyridine–Oxadiazole Conjugates on MIA PaCa‐2 Cell Line

ABSTRACT Pancreatic cancer remains one of the most lethal forms of cancer, with inferior survival rates and very few effective treatment options. To address the challenge, an in silico molecular docking approach was undertaken to design a series of pyridine–oxadiazole–benzonitrile derivatives 5(a–h) against the VEGFR‐2(PDB ID: 4AG8) tyrosine kinase receptor, and exhibited strong binding affinities (−9.4 to −10.8 kcal/mol), some molecules exhibited the stronger binding affinity than the reference inhibitors Axitinib and Lorlatinib. Guided by these results, the molecules were synthesized through a copper(I) iodide‐catalyzed SnAr reaction. The synthesized molecules were purified and subsequently characterized by IR, NMR, and HRMS. The structurally confirmed derivatives were tested for anticancer activity against the human pancreatic cancer cell line Mia PaCa‐2 via the MTT assay. Compounds 5e (IC 50 = 42.01 ± 5.12 µM) and 5c (IC 50 = 59.11 ± 2.96 µM) emerged as the promising molecules among the tested series 5(a–h). A structure–activity relationship study indicated that electron‐withdrawing halogen groups improved activity, whereas bulky or electron‐donating groups reduced it. Overall, the data suggest that halogenated pyridine–oxadiazole–benzonitrile conjugates could serve as valuable leads for continued research in pancreatic cancer treatment.