Synthesis, Anti-Breast Cancer, and EGFR Activity of Novel Pyrido[2,3-d]pyrimidine-piperazine-1,2,4-oxadiazoles.

A variety of new pyrido[2,3-d]pyrimidine-piperazine-1,2,4-oxadiazoles was synthesized and tested in vitro for their ability to inhibit EGFR kinases and their anti-cancer activity against two breast cancer cell lines. Compared to erlotinib, a number of the compounds exhibited acceptable activity. Among them, the most promising compounds 5-(2,4-difluorophenyl)-3-{[4-(pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-1,2,4-oxadiazole, 5-(4-fluorophenyl)-3-{[4-(pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-1,2,4-oxadiazole, and 5-(3,5-dichlorophenyl)-3-{[4-(pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-1,2,4-oxadiazole exhibited excellent anti-cancer activity against MCF-7 cancer cell line with IC50 values of 3.79±0.61, 4.12±0.74 and 4.07±0.39 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.45±0.02, 0.51±0.08 and 0.31±0.07 μM). And also 5-(2,4-difluorophenyl)-3-{[4-(pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-1,2,4-oxadiazole and 5-(4-fluorophenyl)-3-{[4-(pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-1,2,4-oxadiazole shown potent activity against MDA-MB-231 with IC50 values of 5.83±0.88 and 6.32±0.71 μM, respectively. To evaluate the molecular interactions of more potent compounds with the human epidermal growth factor receptor, EGFR (PDB: 4HJO) proteins and a co-crystallized ligand erlotinib. It was observed that all the compounds exhibited greater binding energies in comparison to the standard drug erlotinib. [ABSTRACT FROM AUTHOR]