Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity

Shadia A Galal; Sarah H M Khairat; Fatma A F Ragab; Ahmed S Abdelsamie; Mamdouh M Ali; Salwa M Soliman; Jérémie Mortier; Gerhard Wolber; Hoda I El Diwani

doi:10.1016/j.ejmech.2014.08.048

Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity

Eur J Med Chem. 2014 Oct 30:86:122-32. doi: 10.1016/j.ejmech.2014.08.048. Epub 2014 Aug 15.

Authors

Shadia A Galal¹, Sarah H M Khairat², Fatma A F Ragab³, Ahmed S Abdelsamie², Mamdouh M Ali⁴, Salwa M Soliman⁵, Jérémie Mortier⁵, Gerhard Wolber⁵, Hoda I El Diwani²

Affiliations

¹ Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Dokki, 12622, Cairo, Egypt. Electronic address: sh12galal@hotmail.com.
² Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Dokki, 12622, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
⁴ Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Cairo, Egypt.
⁵ Department of Pharmaceutical Chemistry, Institute of Pharmacy, Freie University Berlin, Koenigin Luise Strasse, Berlin 14195, Germany.

PMID: 25147154
DOI: 10.1016/j.ejmech.2014.08.048

Abstract

On continuation to our work, new quinoxalin-2(1H)-ones were synthesized to study their cytotoxic effect against HepG-2 and MCF-7 with their effect on the human tyrosine kinase (TRK). Compounds 12, 18, 15, 13, 11a, 20 and 16, respectively, were found to be more potent than cisplatin against HepG2 and selective to TRK. Also, compounds 12, 18, 20, 13, 14, and 22, respectively, exhibited decidedly activity against MCF-7 and selectivity against human TRK compared to cisplatin. A molecular docking study was also performed to gain comprehensive understanding into plausible binding modes and to conclude the structure activity relationships of the synthesized compounds. Moreover, anti-inflammatory activity was studied. Compounds 12, 15, 18 and 22 were found to be potent and selective against COX-2.

Keywords: Antitumor activity; Cyclooxygenase-2; Docking; Protein tyrosine kinase; Quinoxalines; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cyclooxygenase 2 / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Hep G2 Cells
Humans
MCF-7 Cells
Molecular Docking Simulation*
Molecular Structure
Quinoxalines / chemical synthesis
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Quinoxalines
Cyclooxygenase 2
Receptor Protein-Tyrosine Kinases