Microwave‐Accelerated C─N Coupling for the Efficient Synthesis of Triazolo[4,3‐b]Pyridazine Derivatives With Potent Cytotoxic Activity and EGFR Inhibitory Potential

Cancer is one of the major public health concerns across the globe, as approximately one in six deaths is due to this fatal disease. Large numbers of efforts are underway throughout the world to discover novel therapeutic agents that can induce potent cytotoxicity even in advanced cancers as drug‐resistant populations. Triazolo‐pyridazine is truly a privileged scaffold as it is part of clinical anticancer agents, including JNJ‐38877605, Volitinib, SGX523, AZD5153, and taletrectinib. In this research, we investigated the preparation of triazolo[4,3‐b]pyridazine derivatives via a microwave‐assisted C─N coupling approach, aiming to optimize the reaction conditions. The microwave‐assisted method presented improved reaction efficiency and yield as compared to conventional methods. The synthesized compounds were evaluated for their cytotoxic activity against HepG2 (liver) and A549 (lung) cancer cell lines. Notably, compound 1d exhibited the most potent cytotoxicity against both HepG2 and A549 cells, with IC50 values of 9.20 and 13.95 µM, respectively. Molecular docking analysis further revealed that compound 1d demonstrated a strong binding affinity of ‐5.04 kcal/mol. This study highlights the successful application of a novel approach for synthesizing triazolo[4,3‐b]pyridazine derivatives and their potential as cytotoxic agents against cancer cells.