Synthesis and Anticancer Properties of Methyl N1-(thien-4-yl) amidrazone-3-carboxylates

Background: A variety of synthetic amidrazones are endowed with antitumor activity. Examples include N1-(thien-3-yl) amidrazone-2-carboxylates that exhibit high potency against breast cancer (MCF-7) and leukemia (K562) cell lines. These results prompted us to design and examine a new set of isomeric N1-(thienyl) amidrazone. Methods: The synthesis of the targeted N1-(thien-4-yl) amidrazone-4-carboxylates 7a-n is achieved via interaction of the appropriate (N-substituted) piperazine with nitrile imine 1,3 dipole (generated in situ from the N1-(thien-4-yl) hydrazonoyl chloride precursor by the action of NEt3). Results: Among the tested compounds 7a-n, the amidrazone (7m) incorporating N4-(pyridin-2yl) piperazine moiety was the most active against leukemia (K562) with IC50 value of 1.02 mu M. Docking studies showed that 7m binds with the oncogenic protein kinase Bcr-Abl. Noteworthy, compound 7m shows negligible cytotoxic effect on human normal fibroblast cells. Conclusion: Compound 7m could probably act as a prospective lead structure for development of new synthetic N1-(thienyl) amidrazones against leukemia (K562).