Design and synthesis of potent 1,2,4-trisubstituted imidazolinone derivatives with dual p38 alpha MAPK and ERK1/2 inhibitory activity

作者：Awadallah Fadi M^*; Abou Seri Sahar M; Abdulla Mohamed M; Georgey Hanan H

来源：European Journal of Medicinal Chemistry, 2015, 94: 397-404.

DOI：10.1016/j.ejmech.2015.03.008

• Imidazolinones
• Breast cancer
• Melanoma
• p38 alpha MAPK
• ERK1/2

The synthesis of new 1,2,4-trisubstituted imidazolinone derivatives was described. The new compounds were designed as dual p38 alpha MAPK 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 p38 alpha MAP, 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.

• 出版日期2015-4-13