Synthesis, Cytotoxicity and Antiproliferative Effect of New Pyrrole Hydrazones

Novel pyrrole-based carbohydrazide (1) and hydrazones (1A-D) were synthesized, characterized, and subjected to spectroscopic studies. The hydrazones were obtained by reacting a pyrrole hydrazide with substituted pyrrole aldehydes. The initial carbohydrazide was prepared by selective hydrazinolysis of the obtained N-pyrrolylcarboxylic acid ethyl ester. The biological activity of the newly synthesized compounds was investigated in vitro on a panel of tumor and non-tumor cell lines. Mouse embryonic fibroblasts BALB 3T3 clone A31 were used in the safety test (BALB 3T3 NRU-assay). Antiproliferative activity was determined on keratinocytes (HaCaT) and melanoma (SH-4) cells by MTT dye reduction assay. The safety test of the compounds showed low cytotoxicity and absence of phototoxic potential. Among our novel pyrrole hydrazones, 1C was the most selective (SI = 3.83) in human melanoma cells and exhibited very good antiproliferative activity (IC₅₀ = 44.63 ± 3.51 μM). The cytotoxic effect of 1C correlates with its ability to induce apoptosis and to cause cell cycle arrest in the S phase. In addition, the results show that hydrazones obtained by condensation with β-aldehydes are more bioactive than those obtained by condensation with α-aldehydes.