Insight on Some Newly Synthesized Trisubstituted Imidazolinones as VEGFR-2 Inhibitors

Abstract

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (<b>3a</b>, <b>3c</b>, <b>3f</b>, <b>3g</b>, <b>3h</b>, <b>3i</b>, <b>3j</b>, <b>6a</b>, <b>6f</b>, and <b>6i</b>) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 μM, compared with Sorafenib and Sunitinib with IC₅₀ values of 0.06 and 0.12 μM, respectively. The most promising candidate, <b>3j</b>, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.