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

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Shaalan M.M.; Osman E.E.A.; Attia Y.M.; Hammam O.A.; George R.F.; Naguib B.H.

Journal: ACS Omega

Publisher: American Chemical Society

Publication Date: 19 August 2024

Volume / Issue: Volume 9 / Issue 35

Pages: 37310–37329

ISSN: 24701343

DOI: 10.1021/acsomega.4c05250

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Shaalan M.M., Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo, 11837, Egypt; Osman E.E.A., Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt; Attia Y.M., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo, 11837, Egypt; Hammam O.A., Pathology Department, Theodor Bilharz Research Institute, Imbaba, Giza, 12411, Egypt; George R.F., Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt; Naguib B.H., Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo, 11837, Egypt, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt

Abstract

A series of novel 3,6-disubstituted pyridazine derivatives were 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. © 2024 The Authors. Published by American Chemical Society.

Citation Information

Scopus Citations: 7

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