Synthesis and Biological Evaluation of Novel 8-Morpholinoimidazo[1,2-a]pyrazine Derivatives Bearing Phenylpyridine/Phenylpyrimidine-Carboxamides.

Herein we designed and synthesized three series of novel 8-morpholinoimidazo[1,2-]pyrazine derivatives bearing phenylpyridine/phenylpyrimidine-carboxamides (compounds -, - and -). All the compounds were evaluated for their IC values against three cancer cell lines (A549, PC-3 and MCF-7). Most of the target compounds exhibited moderate cytotoxicity against the three cancer cell lines. Two selected compounds , were further tested for their activity against PI3Kα kinase, and the results indicated that compound showed inhibitory activity against PI3Kα kinase with an IC value of 1.25 μM. Structure-activity relationships (SARs) and pharmacological results indicated that the replacement of the thiopyranopyrimidine with an imidazopyrazine was beneficial for the activity and the position of aryl group has a significant influence to the activity of these compounds. The compounds - in which an aryl group substituted at the C-4 position of the pyridine ring were more active than - substituted at the C-5 position. Moreover, the cytotoxicity of compounds - bearing phenylpyrimidine-carboxamides was better than that of the compounds -, - bearing phenylpyridine-carboxamides. Furthermore, the substituents on the benzene ring also had a significant impact on the cytotoxicity and the pharmacological results showed that electron donating groups were beneficial to the cytotoxicity.