Ester tethered artemisinin-isatin hybrids: design, synthesis and anti-leukemic activity evaluation

A series of novel artemisinin-isatin hybrids ( 7a-t ) linked via different lengths of esters were designed, synthesized and evaluated for their cytotoxicity against human myeloid leukemia cell lines (K562 and K562/ADR), human acute lymphoblastic leukemia cell line (CCRF-CEM), as well as normal human peripheral blood mononuclear cells (PBMCs) using the MTT assay. The initial results demonstrated that most of the ester-tethered artemisinin-isatin hybrids (IC50: 1.53–51.39 µM) showed activity against CCRF-CEM cells, with six of them (IC50: 3.47–9.52 µM) being >10.5 times more potent than artemisinin (IC50: >100 µM). Notably, hybrid 7i (IC50: 3.82, 1.53, and 22.71 µM) exhibited promising activity against all three tested leukemia cell lines. Hybrid 7i was 3.2 and 2.5 times more active than Adriamycin (IC50: 4.89 µM) and Vorinostat (IC50: 3.83 µM) against K562 cells, respectively, and >4.4 times more effective than Adriamycin (IC50: >100 µM) against K562/ADR cells. Moreover, hybrid 7i (IC50: >100 µM) showed no toxicity towards PBMCs, with an SI value > 26.17, indicating excellent safety and selectivity profiles. Additionally, hybrid 7i displayed acceptable pharmacokinetic properties. In summary, hybrid 7i is a promising lead molecule for the development of novel anti-leukemic agents with low toxicity and high selectivity.