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.

Fadi M Awadallah ¹, Sahar M Abou-Seri ², Mohamed M Abdulla ³, Hanan H Georgey ⁴

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.

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