Synthesis, Bioactivity Evaluation, and Molecular Docking Study of Tranilast Analogs as Anticancer Agents

Abstract:

Developing new agents with higher therapeutic potential and less toxic to overcome the limitations of chemotherapy in cancer treatment has been identified as an urgent need and priority. Recent studies have shown promising anticancer activities of tranilast when used alone or in combination with other chemotherapeutic agents. This research aims to synthesize tranilast analogs, evaluated in vitro anticancer activity, and docked into the TGFβ1 target to find stronger anticancer agents. Tranilast (5a) and analogs (5b–f) were synthesized from anthranilic acid derivatives, Meldrum’s acid, and benzaldehydes based on Knoevenagel-Doebner reaction. The compounds were evaluated for in vitro cytotoxicity activity by MTT assay and docked into the TGFβ1 target using AutoDockTools–1.5.6. Tranilast (5a) and seven analogs (5b–h) were successfully synthesized and analyzed for their structures. Four analogs (5b–d, 5f) possessed stronger effects on both HepG2 and MCF-7 cell lines with proliferation inhibitions at concentrations of 100 µg/mL in the range 41–95% compared to tranilast (16.95% and 22.64%). Compound 5f exhibited the most potent analog with IC₅₀ = 27.57 µg/mL (HepG2) and 16.67 µg/mL (MCF-7) compared to tranilast (IC₅₀ > 100 µg/mL) and had good binding affinity on TGFβ1 target (docking score ˗7.35 Kcal/mol). Four of seven tranilast analogs possessed stronger cytotoxicity activity on both HepG2 and MCF-7 cell lines compared to that of the parent compound, tranilast. Notably, compound 5f displayed the most potent activity and good binding affinity on the TGFβ1 target, indicating the potential for further study as an anticancer agent.

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