Evaluation of anticancer properties of amide bridged artesunate derivatives

Cancer continues to be one of the most common causes of death worldwide. The challenges in its treatment arise from the biological diversity of the disease and its ability to develop resistance to conventional therapies. Therefore, the discovery of new drug candidates is of great importance. In this study, artesunate a compound widely used in malaria treatment and also reported to have anticancer effects was hybridized with biologically active heterocyclic scaffolds such as benzofuran, piperidine, carbazole, and indole through amide bonds to design and synthesize novel hybrid molecules. The anticancer activities of the synthesized hybrid compounds were evaluated in various human cancer cell lines, including colon (Caco-2), prostate (LnCap), liver (HepG2), lung (A549), endometrial (Ishikawa), breast (MDA-MB231), and thyroid (TT). In this context, cytotoxicity, apoptosis induction, cell invasion, migration, and colony formation potentials were investigated. Additionally, the anti-inflammatory properties of the derivatives were studied in the mouse macrophage cell line RAW264.7. Artesunate-benzofuran derivatives exhibited strong and selective cytotoxic effects, with EC50 values ranging from 12–248 μM for Caco-2, 1.37–139 μM for LnCap, 1.30–233 μM for HepG2, 7.8–223 μM for Ishikawa, 4–108 μM for TT, 21–206 μM for MDA-MB231, and 60–328 μM for A549. The EC50 values of artesunate-piperidine derivatives ranged from 3.25–163.3 μM in different cell lines, while artesunate-carbazole and -indole derivatives showed EC50 values between 53.6–141.5 μM. The tested hybrid compounds were shown to induce apoptosis by activating pro-apoptotic genes such as BAX, CASP3, CASP8, CASP9, and P53; and to inhibit cell migration by suppressing MMP-2 and MMP-9 gene expression. Additionally, they significantly suppressed colony formation abilities. In the inflammation model, all derivatives were found to reduce nitric oxide production in LPS-stimulated RAW264.7 cells and to modulate the expression of inflammatory markers including COX-2, iNOS, TNF-α, IL-6, and IL-10. In conclusion, the synthesized artesunate-based hybrid molecules exhibited both anticancer and anti-inflammatory potential. Therefore, further in vivo studies are recommended to evaluate their potential as multifunctional therapeutic agents.