Abstract
Recently, the diarylurea scaffold has been used widely to design potential anticancer agents. Pursuing our design strategy based on the modification of sorafenib as the lead compound using de novo design approaches, a new series of diaryl urea derivatives were synthesized through an efficient sequential one-pot reaction and evaluated for their in vitro antiproliferative activities against A549 and HT-29 cell lines. Notably, compound 11j exhibited antiproliferative activity against HT-29 with an IC50 value of 17.87 µM. SAR analyses revealed that substitution of the core diaryl scaffold with chlorine and methyl groups, and linear elongation of the molecules by the introduction of a methylene spacer group could cooperatively improve antiproliferative activity. The most active compound 11j induced mild apoptosis in HT-29 cells assessed based on DAPI staining experiments. The results of molecular docking simulations showed that the novel compounds bind to VEGFR-2 in a similar fashion to that observed for sorafenib. Molecular docking calculations also revealed that the most active compound 11j can bind well to the active site of VEGFR-2 by forming various interactions similar to those known for sorafenib particularly the π–π interaction, which is almost unique to sorafenib and highly active derivatives.
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Acknowledgements
The authors would like to thank the Biotechnology Research Center and the Research Office of Tabriz University of Medical Sciences for providing financial support under the Postgraduate Research Grant scheme for the PhD thesis of FA (Grant number 58079). The kind support by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 62491) is also appreciated.
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Azimian, F., Hamzeh-Mivehroud, M., Shahbazi Mojarrad, J. et al. Facile one-pot sequential synthesis of novel diaryl urea derivatives and evaluation of their in vitro cytotoxicity on adenocarcinoma cells. Med Chem Res 30, 672–684 (2021). https://doi.org/10.1007/s00044-020-02673-7
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DOI: https://doi.org/10.1007/s00044-020-02673-7