Triazolopyridazine derivatives: Synthesis, cytotoxic evaluation, c-Met kinase activity and molecular docking

Eman M Ahmed; Nadia A Khalil; Azza T Taher; Rana H Refaey; Yassin M Nissan

doi:10.1016/j.bioorg.2019.103272

Triazolopyridazine derivatives: Synthesis, cytotoxic evaluation, c-Met kinase activity and molecular docking

Bioorg Chem. 2019 Nov:92:103272. doi: 10.1016/j.bioorg.2019.103272. Epub 2019 Sep 10.

Authors

Eman M Ahmed¹, Nadia A Khalil¹, Azza T Taher², Rana H Refaey³, Yassin M Nissan⁴

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, October 6 University, Giza, Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt. Electronic address: rhosny@msa.eun.eg.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt.

PMID: 31539742
DOI: 10.1016/j.bioorg.2019.103272

Abstract

Novel series of some triazolo[4,3-b]pyridazine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated for their cytotoxic activity at 10^-5 M concentration towards 60 cancer cell lines according to USA NCI protocol. Most of the synthesized compounds showed good activity against SR (leukemia) cell panel. The most active compounds, 2f and 4a were subjected for further evaluation at a five dose level screening and their efficacy for c-Met kinase inhibition was determined in vitro. Binding mode of these derivatives was explored via molecular docking.

Keywords: Cytotoxic activity; Pyridazines; Triazolopyridazines; c-Met kinase.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridazines
Proto-Oncogene Proteins c-met