Dihydroartemisinin-Chloro/Bromoisatin Hybrids: Design, Synthesis, and Anti-Breast Cancer Evaluation

Twelve dihydroartemisinin-chloro/bromoisatin hybrids were synthesized by combining dihydroartemisinin with chloro/bromoisatin and their in vitro anti-proliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR, and MDA-MB-231/ADR breast cancer cell lines was evaluated. A significant part of the synthesized hybrids exhibited significant anti-breast cancer activity against the tested cell lines and showed potential in overcoming drug resistance. 2-{4-Bromo-2-oxo-1-[4-({(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl}oxy)butyl]indolin-3-ylidene}hydrazine-1-carbothioamide was found to be the most potent among all the synthesized hybrids, with IC₅₀ values of 28.6–39.4 µM against the four breast cancer cell lines, and the activity was more than 2.53 times greater than that of adriamycin (IC₅₀ >100 µM) against multidrug-resistant MCF-7/ADR and MDA-MB-231/ADR cancer cell lines. A preliminary structure-activity relationships (SARs) analysis indicated that chloro/bromo substitution at the C⁶ position of the isatin moiety was more favorable than at the C⁴ position; the substituents at the C³ position of the isatin moiety and the carbon spacers between DHA and isatin moieties appeared to play a more significant role. The enriched SARs obtained from this study may provide useful information for the rational design of dihydroartemisinin-isatin hybrids with improved anti-breast cancer activity and drug resistance overcoming capabilities.