Background: Hydroxyurea (HU) is used to treat cancer. HU has a short half-life due to its
small molecular weight and high polarity, therefore a high dosage of the drug should be used which
introduces side effects and more rapid development of resistance.
Objective: The objective of the current study is to design new lipophilic analogues of hydroxyurea with
higher stability and better cell penetration. The designed compounds were synthesized and then evaluated
in terms of their cytostatic activities against two human cell lines.
Methods: The synthesis of designed ligands was achieved via two-step procedure. Detail of the synthesis
and chemical characterization of the analogs are described. The cytotoxic activity of the designed
ligands was evaluated in vitro against two different cancer cell lines at 24 and 48h using MTT test.
Results: Based on the IC50 values, all the designed and prepared compounds were more potent than
hydroxyurea at 24 and 48h on both cell lines that the cytostatic activity at 48h was more than 24h.
Drug-receptor interactions study indicated compound 7 as the most potent ligand, tightly bonded to
surrounding amino acids in the active site of receptor via two strong hydrogen bonds and some hydrophobic
Conclusion: Compound 7 with the suitable volume, log p and shape is the most active ligand against
both cell lines. It is concluded or suggested that the size, shape and hydrophobic character of substituents
strongly affect the pharmacodynamics and pharmacokinetics of these type of ligands.