Design and synthesis of potent 1,2,4-trisubstituted imidazolinone derivatives with dual p38αMAPK and ERK1/2 inhibitory activity

Fadi M Awadallah; Sahar M Abou-Seri; Mohamed M Abdulla; Hanan H Georgey

doi:10.1016/j.ejmech.2015.03.008

Design and synthesis of potent 1,2,4-trisubstituted imidazolinone derivatives with dual p38αMAPK and ERK1/2 inhibitory activity

Eur J Med Chem. 2015 Apr 13:94:397-404. doi: 10.1016/j.ejmech.2015.03.008. Epub 2015 Mar 5.

Authors

Fadi M Awadallah¹, Sahar M Abou-Seri², Mohamed M Abdulla³, Hanan H Georgey⁴

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt. Electronic address: fadi_mae@hotmail.com.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt. Electronic address: saharshaarawy_69@yahoo.com.
³ Research Unit, Saco Pharm. Co., 6th October City, Egypt.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt.

PMID: 25778995
DOI: 10.1016/j.ejmech.2015.03.008

Abstract

The synthesis of new 1,2,4-trisubstituted imidazolinone derivatives was described. The new compounds were designed as dual p38αMAPK and ERK1/2 inhibitors through hybridization of pharmacophoric elements associated with inhibition of these kinases. The kinase inhibition assay revealed excellent activity in the nanomolar range; especially compounds 6d and 7h which seemed promising candidates for such dual activity with IC50 values of 4.5 and 4.7 nM against p38αMAP, 25.0 and 24.0 nM against ERK1, and 3.2 and 3.5 nM against ERK2, respectively. These compounds were further tested for their antiproliferative activity against nine cancer cell lines, where they elicited high activity in the sub-micromolar range against breast, prostate and melanoma cells.

Keywords: Breast cancer; ERK1/2; Imidazolinones; Melanoma; p38αMAPK.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Imidazolines / chemical synthesis
Imidazolines / chemistry
Imidazolines / pharmacology*
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 3 / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Antineoplastic Agents
Imidazolines
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases