Novel 3,6-disubstituted pyridazine derivatives targeting JNK1 pathway: Scaffold hopping and hybridization-based design, synthesis, molecular modeling, in vitro and in vivo anticancer evaluation.

Authors

Mai M. Shaalan, The British University in EgyptFollow
Essam Eldin A. Osman, Cairo UniversityFollow
Yasmeen M. Attia, The British University in EgyptFollow
Olfat A. Hammam, theodor Bilharz Research InstituteFollow
Riham F. George, Cairo UniversityFollow
Bassem H. Naguib, The British University in EgyptFollow

Document Type

Article

Publication Date

Summer 8-19-2024

Abstract

A series of novel 3,6-disubstituted pyridazine derivatives was designed, synthesized, and biologically evaluated as preclinical anticancer candidates. Compound 9e exhibited the highest growth inhibition against most of the NCI-60 cancer cell lines. The in vivo anticancer activity of 9e 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 9e 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 9e and prove its stability in the JNK1 binding pocket.

Recommended Citation

Shaalan, Mai M.; Osman, Essam Eldin A.; Attia, Yasmeen M.; Hammam, Olfat A.; George, Riham F.; and Naguib, Bassem H., "Novel 3,6-disubstituted pyridazine derivatives targeting JNK1 pathway: Scaffold hopping and hybridization-based design, synthesis, molecular modeling, in vitro and in vivo anticancer evaluation." (2024). Pharmacy. 811.
https://buescholar.bue.edu.eg/pharmacy/811