Green sonosynthesis of novel pyrazolone-fused heterocycles catalyzed by a hydroxyl-functionalized ionic liquid: Discovery of a potent anticancer lead

This study describes the design and synthesis of novel pyrazolone-based heterocycles, exploiting the pyrazole scaffolds’ established pharmacological profile to develop potent anticancer agents. A green chemistry approach was employed, with the key transformation achieved through a highly efficient Knoevenagel condensation catalyzed by the hydroxyl-functionalized ionic liquid [DABCO-EtOH][OAC], which exhibited exceptional catalytic performance in a water-composite medium. This environmentally benign, reusable, and high-yielding method enabled the synthesis of the crucial synthon, 1-phenyl-4-(thiophen-2-ylmethylene)pyrazolidine-3,5-dione. Subsequent sonochemical reactions of this synthon afforded a diverse library of polycyclic frameworks, including
pyrano[2,3-c]pyrazoles
and fused pyrazolopyranopyrimidines. All synthesized derivatives were fully characterized by elemental analysis, thin-layer chromatography (TLC), and spectroscopic methods (Fourier transform infrared (FT-IR), mass spectrometry (MS), and nuclear magnetic resonance (NMR)). Biological evaluation revealed strong
in vitro
cytotoxic activity against HepG-2, MCF-7, and A-549 cell lines. Notably, compounds
6, 8
, and
9
exhibited remarkable potency, displaying IC₅₀ values comparable to or superior to that of the reference drug, doxorubicin. Among them, compound
8
was the most active, with IC₅₀ values of 1.93, 2.42, and 1.59 µg/mL against the respective cell lines. These findings underscore both the efficacy of the green synthesis methodology and the promise of these novel pyrazolone derivatives as potential anticancer leads.