Background: Cancer is one of the most important global public health issues and although we have made significant progress in the diagnosis and treatment, it remains a serious challenge for modern medicine.

Aim: Rationally design and synthesize three thiourea derivatives (IVa–IVc) that may preserve the selective anticancer efficacy and relatively low toxicity of roscovitine and achieve enhanced pharmacokinetic properties.

Methodology: Target derivatives were sequentially synthesized, characterized by FT-IR, NMR and EI-MS, and tested for antiproliferative activity against MCF-7 cells by MTT assay, with IC₅₀ values relatively to roscovitine.

Results: Potent antiproliferative activities were observed against MCF-7 breast cancer cells with a series of thiourea derivatives (IVa–IVc). IVa and IVb were the best inhibitors (78.13% vs 97.87% for rescovitine with an IC50 of 15.9 μM; 75.23% vs 97.87% for rescovitine with an IC50 of 15,9 μM) among the synthesized compounds while all derivatives synthesized were predicted to have a good drug-likeness according to Lipinski´s Rule of Five as well as high gastrointestinal absorption. The cytotoxic activity of derivatives correlated to substituents in structure–activity relationship analysis, confirming that both electron-donating and electron-withdrawing substituents were beneficial for biological efficacy. 

Conclusion: VIa and VIb appeared as lead candidates with comparably high cytotoxicity to rescovitine. VIa, when substituted with fluorine, showed the most activity and useful structure–activity relationships were featured for obtaining further derivatives with greater potency.