Novel 3,6-Disubstituted Pyridazine Derivatives Targeting JNK1 Pathway: Scaffold Hopping and Hybridization-Based Design, Synthesis, Molecular Modeling, and <i>In Vitro</i> and <i>In Vivo</i> Anticancer Evaluation

A series of novel 3,6-disubstituted pyridazine derivatives were designed, synthesized, and biologically evaluated as preclinical anticancer candidates. Compound <b>9e</b> exhibited the highest growth inhibition against most of the NCI-60 cancer cell lines. The <i>in vivo</i> anticancer activity of <b>9e</b> was subsequently investigated at two dose levels using the Ehrlich ascites carcinoma solid tumor animal model, where a reduction in the mean tumor volume allied with necrosis induction was reported without any signs of toxicity in the treated groups. Interestingly, compound <b>9e</b> was capable of downregulating c-jun N-terminal kinase-1 (JNK1) gene expression and curbing the protein levels of its phosphorylated form, in parallel with a reduction in its downstream targets, namely, c-Jun and c-Fos in tumors, along with restoring p53 activity. Furthermore, molecular docking and dynamics simulations were carried out to predict the binding mode of <b>9e</b> and prove its stability in the JNK1 binding pocket.