Structure–activity relationship guided design, synthesis and biological evaluation of novel diaryl urea derivatives as antiproliferative agents

Diaryl urea-based compounds have attracted the attention of many researchers due to their potential as anticancer agents. Following our previous study on a series of diaryl urea compounds and implementation of the obtained structure activity relationship (SAR) analysis, a new set of derivatives were designed and synthesized. The synthesized compounds were subjected to evaluation for their in vitro antiproliferative activities against A549 and HT-29 cell lines. Among all, 6a emerged as the most potent antiproliferative agent with an IC₅₀ value of 15.28 and 2.566 µM against HT-29 and A549 cells, respectively. Comparing the activity of the newly designed and synthesized diaryl urea compounds 4a-b and 6a-e with those for the previously reported compounds 8a-b and 9a-f confirmed the importance of the substitution of amide groups instead of ester between the central and distal benzene rings of diaryl urea scaffold. The results of current study revealed that the substitution of proximal and distal benzene rings with chlorine and methyl groups, alongside the linear extension of molecules through the introduction of a methylene spacer group could enhance antiproliferative activity, which is in agreement with previously reported SAR analysis. Molecular docking simulations demonstrated that all designed compounds exhibit binding affinity to VEGFR-2 similar to that observed experimentally for sorafenib. The findings of this study may offer valuable insights for the further development of diaryl urea-based anticancer agents.