Molecular Docking Approach For Design and Synthesis of Thioxanthone Derivatives as Anticancer Agents

Abstract

Thioxanthone derivatives were docked, synthesized, and tested for their anticancer activity. The molecular docking results showed that 1-hydroxythioxanthone, 2-chloro-1-hydroxythioxanthone, and 4-chloro-1-hydroxythioxanthone gave lower binding energy than erlotinib demonstrating that those thioxanthones have stronger interaction in the active site of EGFR protein. The addition of one hydroxyl and chloro groups on 1-hydroxythioxanthone greatly enhanced its inhibition in EGFR protein. All thioxanthone derivatives had hydrogen bonding interaction with MET769 residue. The in vitro anti-cancer assay against all cancer cells (T47D, HeLa, WiDr, A549) revealed that 2-chloro-1-hydroxythioxanthone and 4-chloro-1hydroxythioxanthone gave lower IC 50 than 1-hydroxythioxanthone due to the addition of one chloro substituent. Meanwhile, 1,3-dihydroxythioxanthone exhibited the strongest anticancer activity, as well as the highest selectivity index (3.22-19.55) among the other thioxanthones. Based on these findings, 1,3-dihydroxythioxanthone is a potential anticancer drug candidate for further development in the future.

In silico Approach for Design, Synthesis and Biological Evaluation of Tioxanthone Derivatives as Potential Anticancer Agents

“…The synthesis was carried out by bromination of the 1,3-dihydroxythioxanthone (TX10) obtained from our previous study. [10] A mixture of 1,3-dihydroxythioxanthone (0.1 g, 0.4 mmol), potassium bromate (KBrO 3 ) (0.025 g), hydrobromic acid (HBr) (1 mL), and acetic acid (CH 3 COOH) (1 mL) was stirred at room temperature for 2 hours and monitored by TLC. After completion, the reaction mixture was poured into crushed ice and then stirred for 30 minutes at room temperature.…”

“…Our previous study provided 1,3-dihydroxythioxanthone (TX10), which was then subjected to chlorination to synthesize the product. [10] To achieve this, a mixture was performed of the obtained from our previous study A mixture of 0.122 g (0.5 mmol) of 1,3-dihydroxythioxanthone, 0.08 g of N-Chlorosuccinimide (NCS), and 3 mL hydrochloric acid (HCl) was stirred at room temperature for 2 hours with monitoring by TLC. Upon completion, the reaction mixture was poured into crushed ice and stirred for 30 minutes at room temperature.…”

“…[6][7][8][9] The anticancer activity of thioxanthones is determined by the position and number of substituents in its scaffold. In a study conducted by Hermawan et al (2022), it was discovered that adding one hydroxyl and one chloro group to thioxanthone enhanced their anticancer activity against WiDr, Hela, A549, and T47D cancer cells. [10] In 2022, Fatmasari et al reported enhanced anticancer activity of a xanthone bearing hydroxyl group against HeLa, WiDr, and MCF7 cancer cell lines.…”

“…In a study conducted by Hermawan et al (2022), it was discovered that adding one hydroxyl and one chloro group to thioxanthone enhanced their anticancer activity against WiDr, Hela, A549, and T47D cancer cells. [10] In 2022, Fatmasari et al reported enhanced anticancer activity of a xanthone bearing hydroxyl group against HeLa, WiDr, and MCF7 cancer cell lines. [11] Meanwhile, studied by Yuanita et al (2019Yuanita et al ( , 2021 found that adding a chloro substituent to hydroxyxanthone derivatives enhanced anticancer activity against T47D and HeLa cancer cells, and the addition of a bromo substituent improved efficacy against P388 cancer cells.…”

“…In a study conducted by Hermawan et al. (2022), it was discovered that adding one hydroxyl and one chloro group to thioxanthone enhanced their anticancer activity against WiDr, Hela, A549, and T47D cancer cells [10] . In 2022, Fatmasari et al.…”