Design, synthesis and cytotoxic evaluation of 4-methylidenepyrazolidin-3-ones

• Three series of, so far unknown, 4-methylidenepyrazolidin-3-ones were synthesized.
• Cytotoxicity of the synthesized pyrazolidinones was evaluated.
• The most active compounds have IC50 values below 5 μM.
• Additional nitrogen atom in the α-methylidene-γ-lactam ring enhances cytotoxicity.

Three series of new 4-methylidenepyrazolidin-3-ones with various substitution patterns were synthesized and tested for the cytotoxic activity against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer cell line. Several obtained methylidenepyrazolidinones exhibited high cytotoxic activity with IC50 values below 10 μM, mainly against HL-60 leukemia cell line and two of them, 18d,e, displayed IC50 ≤ 5 μM, against all tested cell lines. Structure–activity relationship studies revealed that the presence of phenyl substituents on both ring nitrogen atoms and vinyl or phenyl substituents in position 5 are crucial for high activity. Selected methylidenepyrazolidinones were also tested on normal human umbilical vein endothelial cells (HUVEC) and pyrazolidinone 18a was found to be 5-fold more toxic against HL-60 than normal cells.

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