Synthesis, molecular docking, molecular dynamics, pharmacokinetics prediction and bioassay of N-(phenylcarbamothioyl)-4-chlorobenzamide as anti-breast cancer candidate

Context: Breast cancer ranks as the leading cause of mortality among women in Indonesia. Thiourea is a compound containing sulfur atom and nitrogen in which its chemical structure resembles urea compound, which has been applied as an anticancer, such as hydroxyurea, nitrosourea, 5-fluorouracil, and sorafenib. Aims: To develop anticancer candidates as a new compound of thiourea derivative, N-(phenylcarbamothioyl)-4-chloro-benzamide (4-Cl-PCTB). Methods: The compound was synthesized from phenylthiourea and 4-chloro-benzoyl chloride by applying nucleophilic acyl substitution reactivity. The compound resulting from synthesis was examined for its purity and structure identification by using FTIR, 1H-NMR,13C-NMR, and MS. In silico tests included molecular docking using Molexus software, molecular dynamics simulation using Desmond and MOE software, and pharmacokinetics prediction using SCFbio, pkCSM, and Swiss ADME. Anticancer activity through cytotoxic test was done using the MTT method in T47D cancer cells and Vero normal cells. Results: The 4-Cl-PCTB compound was obtained from the synthesis. The results of the molecular docking and molecular dynamics simulation on the checkpoint kinase 1 receptor (2YWP) showed a plant score of -67.19 kcal/mol, which was better than the native ligand and the standard reference hydroxyurea. The molecular dynamics simulation results indicated that the 4-Cl-PCTB compound exhibited better bond stability compared to hydroxyurea. Pharmacokinetic predictions for 4-Cl-PCTB showed good GIT absorption, classifying it under BCS Class I, with a low volume of distribution, no BBB penetration, a half-life of 3 hours, and no hepatotoxicity. The results of the cytotoxic test: IC50 T47D cells = 0.44 mM, Vero cells = 76.10 mM, hydroxyurea = 4.58 mM. SI value = 173.35 (SI >10). Conclusions: 4-Cl-PCTB is possible to be an anticancer candidate drug better than hydroxyurea.