Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach

To develop inhibitors blocking VEGFR2/KDR/Flk-1 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was generated and expanded. Considering in silico binding affinity towards VEGFR2/KDR/Flk-1, synthetic feasibility, and drug-likeness property, some of the designed ligands were selected for synthesis and screening for their in vitro antiproliferative activities against two Cancer cell lines (HT-29 and A549). Four compounds (13a, 14a, 14l and 15b) exhibited stronger antiproliferative activity (with IC₅₀ values of 13.27, 6.62, 12.74, 3.38 μM, respectively) against HT-29 cells compared to that of the positive reference drug sorafenib (IC₅₀ = 17.28 μM). Notably, compound 15b demonstrated the highest activity, and in particular, it induced HT-29 Apoptosis, increased intracellular Reactive Oxygen Species level, arrested cell cycle at G0/G1 phase, and influenced the expression of apoptosis- and cell cycle-related proteins. 15b compound can effectively block the Raf/MEK/ERK pathway and inhibit VEGFR2/KDR/Flk-1 phosphorylation. Molecular docking revealed that 15b can bind well to the active site of VEGFR2/KDR/Flk-1 receptor. Collectively, 15b may be considered as a promising compound amenable for further investigation for the development of new Anticancer agents.