Multitarget Anticancer and Anti-Inflammatory Properties of a Novel Artesunate–Indole Hybrid: Synthesis and Functional Evaluation

Abstract

An amide-bridged artesunate–indole hybrid molecule (TRY–ART) was investigated for its anticancer and anti-inflammatory activities. Cytotoxicity studies revealed that TRY–ART exhibited significant cytotoxicity against Caco-2, LNCaP, HepG2, Ishikawa, and A549 cancer cell lines, with EC₅₀ values of 120.2 ± 1.14, 79 ± 0.54, 137.9 ± 0.78, 94 ± 2.37, and 183 ± 1.65 µM, respectively. Apoptosis analysis demonstrated that TRY–ART significantly induced apoptotic events in all tested cancer cell lines. It revealed its pro-apoptotic potential by upregulating the expression levels of pro-apoptotic genes (BAX, CASP3, CASP8, CASP9, and P53) and downregulating the anti-apoptotic gene BCL2. Colony-formation assays showed a reduction in colony formation capacity, and wound-healing assays indicated its efficacy against cell migration. qRT-PCR analysis revealed strong anti-migration effects by downregulating migration-related genes (MMP2 and MMP9) and upregulating their inhibitors (TIMP1 and TIMP2). Furthermore, anti-inflammatory evaluation by the Griess method in Lipopolysaccharide (LPS)-induced RAW264.7 macrophages revealed that TRY–ART suppressed nitric oxide production by 35% and significantly downregulated pro-inflammatory genes (Cox-2, Inos, Tnf-α, and Il6) while upregulating the anti-inflammatory gene Il10. In conclusion, the newly synthesized amide-bridged artesunate–indole hybrid molecule, TRY–ART, exhibits promising anticancer and anti-inflammatory properties.