DINI KESUMA (2018) PEMODELAN MOLEKUL, SINTESIS SENYAWA N-BENZOIL-N’-FENILTIOUREA DAN 12 TURUNANNYA SERTA HUBUNGAN KUANTITATIF STRUKTUR-AKTIVITAS SITOTOKSIK PADA SEL KANKER MCF-7. Disertasi thesis, UNIVERSITAS AIRLANGGA.

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Abstract

Thiourea derivatives are one of the promising anticancer groups to be developed further. These derivatives act as an EGFR inhibitor by inhibiting Tyrosine Kinase Receptors (RTKs) in the intracellular region. In this study, a new compound of thiourea derivative, namely N-benzoyl-N'-phenylthiourea (BFTU) compound, was synthesized from N-phenylthiourea through an acylation reaction with benzoyl chloride. In addition, it also synthesized 12 BFTU derivatives compounds, namely: 2-Cl-BFTU; 3-Cl-BFTU; 4-Cl-BFTU; 2,4-Cl2-BFTU; 3,4-Cl2-BFTU; 4-Br-BFTU; 4-F-BFTU; 4-NO2-BFTU; 4- CH3-BFTU; 4-OCH3-BFTU; 4-CF3-BFTU and 4-t-butyl-BFTU. Synthesis of 13 compounds was carried out through a single step reaction and the structure of the synthesis result was confirmed using IR, 1H-NMR, 13C-NMR, HRMS. The study began with the prediction of activity, bioavailability and toxicity where those 13 compounds demonstrated biological activities on anticancer receptor with bioavailability value above 80% and toxicity range of 541.311-859.827 mg/Kg BW. The molecular modeling used to predict the activity was docking between 13 test compounds with Epidermal Growth Factor Receptor (EGFR) (PDB code : 1M17) using the Molegro Virtual Docker (MVD) program. The RS value of BFTU compound and its 12 derivatives is within the range of -76.3909-(-90.8638) kcal/mol and the RS value of Hydroxyurea (HU) is -38.4495 kcal /mol. The smaller the RS value, the more stable the bond between the ligand and the receptor and it is predicted that the biological activity will increase. To determine the IC50 cytotoxic activity of BFTU compound and its 12 derivatives, in vitro activity test was conducted against breast cancer cells MCF-7 and their selectivity in Vero normal cells. BFTU compound and its 12 derivatives showed higher cytotoxic activity on MCF-7 cells than HU compound and 12 BFTU derivatives showed higher cytotoxic activity than erlotinib. BFTU compound and its 12 derivatives also showed selectivity values of 59 to 1.790 times more selective work on MCF-7 breast cancer cells. It can be concluded that BFTU compound and its 12 derivatives are toxic to MCF-7 cells, but selective or not toxic to Vero normal cells. Based on the linear regression statistical calculation, the equation was obtained between the in silico test (RS) and the in vitro test (Log 1/IC50) of 13 compounds, where there was a significant relationship between the value of RS and Log 1/IC50. The best QSAR equation is the QSAR equation three parameters, namely: Log 1/IC50 = 0.200 π2 – 0.383 π + 0.343 σ – 0.129 Es + 0.504 (n = 13; r = 0.815; SE = 0.18086; F = 3.966; Sig = 0.046). The best QSAR equation obtained can be used to design other BFTU derivative compounds, which have better anticancer activity.

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