Synthesis and cytotoxic activity of N-(4-bromo)-benzoyl-N’phenylthiourea and 4-(tert-butyl)-N-benzoylurea on primary cells of HER2-Positive breast cancer

Abstract

Many of the breast cancer treatments use chemotherapeutic agents in the form of synthetic drugs. Some thiourea and benzoylurea derivatives have been proven to inhibit the proliferation of breast cancer cells. Up until now, the derivation compounds are still being developed. In this study, we synthesized two compounds namely N-(4-bromo)-benzoyl-N'-phenylthiourea and 4-(tert-butyl)-N-benzoylurea. Before the two compounds were synthesized, the prediction of cytotoxic activity in silico was first performed by docking the synthesis compounds with the HER2 receptor (PDB code: 3PP0). The results of the in-silico test are Rerank Score (RS) value using the MVD program (Molegro Virtual Doker). Acyl nucleophilic substitution was carried out to synthesize the compounds. The structure of the synthesized compounds was identified using FTIR, 1H-NMR, 13C-NMR and Mass Spectrometry. In vitro cytotoxic activity was carried out on HER2-positive primary breast cancer cells and produced IC50 values. The results showed that the RS value of N-(4-bromo)-benzoyl-N'-phenylthiourea was smaller (-99.21kcal/mol) than 4-(tert-butyl)-N-benzoylurea (-88.86kcal/mol), meanwhile the RS value of hydroxyurea as a comparison compound which has a urea group and anticancer activity of -34.60kcal/mol. IC50 values of N-(4-bromo)-benzoyl-N’-phenylthiourea and 4-(tert-butyl)-N-benzoylurea were 0.54 mM and 0.61mM respectively. Hydroxyurea had an IC50 value of 11.61mM. It can be concluded that N-(4-bromo)-benzoyl-N’-phenylthiourea was more potent than 4-(tert-butyl)-N-benzoylurea so it can be developed further as an anticancer candidate for HER2-positive breast cancer.