Design, synthesis and biological evaluation of 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1.

Fibroblast growth factor receptor 1 (FGFR1) plays an important role in tumorigenesis and is therefore an attractive target for anticancer therapy. Using molecular docking approach we have identified inhibitor of FGFR1 belonging to 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones with IC50 value of 3.5 μM. A series of derivatives of this chemical scaffold has been synthesized and evaluated for inhibition of FGFR1 kinase activity. It was revealed that the most promising compounds 5-amino-1-(3-hydroxy-phenyl)-4-(6-methyl-1H-benzoimidazol-2-yl)-1,2-dihydro-pyrrol-3-one and 5-amino-4-(1H-benzoimidazol-2-yl)-1-(3-hydroxy-phenyl)-1,2-dihydro-pyrrol-3-one inhibit FGFR1 with IC50 values of 0.63 and 0.32 μM, respectively, and posses antiproliferative activity against KG1 myeloma cell line with IC50 values of 5.6 and 9.3 μM. Structure-activity relationships have been studied and binding mode of this chemical class has been proposed.