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

Abstract

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.

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