Synthesis, characterization, and biological evaluations of substituted phenethylamine-based urea as anticancer and antioxidant agents

Cancer is one of the most important diseases. It is the second leading cause of death worldwide following cardiovascular disease. There is a need to develop new chemotherapeutic agents for the treatment of cancer and it is still a significant task for medicinal chemists. Symmetrical and unsymmetrical urea derivatives have been reported to play a significant role in biological systems. Phenethylamine is a precursor of dopamine and related compounds. In this study, we disclose the first examples of phenethylamine-based urea derivatives bearing fluoro, methoxy, and methyl groups. We also report cytotoxicity and toxicity profiles of novel urea derivatives on HeLa (human cervical cancer), A549 (non-small cell lung carcinoma), and HDF (human dermal fibroblast) cell lines. Moreover, we demonstrate antioxidant properties of synthesized compounds by DPPH, ABTS, and CUPRAC method. The results revealed that 1,3-bis(4-methylphenethyl)urea was up to eightfold more potent than cisplatin against HeLa cell line and also displayed very low toxic effect on HDF cell line compared to cisplatin. On the other hand, the anticancer activity of 1-(3,4-dimethoxyphenethyl)-3-(4-fluorophenethyl)urea and 1-(3,4-dimethoxyphenethyl)-3-(4-methylphenethyl)urea were close to that of cisplatin on A549 cell line, although 1-(3,4-dimethoxyphenethyl)-3-(4-fluorophenethyl)urea was more toxic than compound 1-(3,4-dimethoxyphenethyl)-3-(4-methylphenethyl)urea on HDF cell line. All tested compounds displayed remarkable activity compared to the standard antioxidants. Considering these properties, they may be a lead compounds for the treatment of human cervical and non-small cell lung cancer. These findings may be helpful for the discovery of more biologically active phenethylamine-based urea for clinical studies. Graphic abstract: