Synthesis and Evaluation of 5-(3-(Pyrazin-2-yl)benzylidene)thiazolidine-2,4-dione Derivatives as Pan–Pim Kinases Inhibitors

摘要

Pim kinases play a key role in the regulation of signaling pathways including proliferation, migration, and metabolism and are a potential target for cancer therapy. A series of 5-benzylidenethiazolidine-2,4-diones were synthesized as pim kinase inhibitors. The structure–activity relationships (SAR) of the analogues in inhibiting in vitro pim kinase activity as well as the proliferation of leukemia cell lines were examined. SAR studies indicated that a hydroxyl group at the 2-position of the benzene ring of 5-benzylidenethiazolidine-2,4-dione plays an important role in the inhibitory activity against all three pim kinases and replacement with a pyrazinyl group at the 5-position of the benzene ring of 5-benzylidenethiazolidine-2,4-dione improved activity significantly. The compounds exerted anti-proliferative activity against the three leukemia cell lines we tested. The most potent compound, 5i , had an EC₅₀ value of 0.8?μM in the MV4-11 cell line. The result of kinase profiling indicated that compound 5i was highly selective for pim-kinases.