Design, synthesis, molecular docking, and cytotoxic studies of new pyrimidine analogs as potent anticancer agents

Abstract Background In this work, a novel and greenly synthesized Ag/TiO 2 @graphite nanocatalyst was utilized as an efficient heterogeneous catalyst for the synthesis of a series of pyrazolopyrimidine derivatives with promising potential antioxidant and anticancer activities. Methods The nanocatalyst was prepared through a green protocol using Rosmarinus officinalis leaves extract and applied for catalyzing the condensation of enaminones with hydrazides under thermal conditions. The antioxidant and anticancer activities were assessed by DPPH and MTT assays. Results The nanocatalyst was characterized by UV–visible, FTIR, zeta potential, HR‐TEM, and XRD analyses. Alternatively, the nanocatalyst demonstrated improved catalytic performance in the synthesis of a series of pyrazolopyrimidine derivatives, yielding high yields (86–97%) within short reaction times. FTIR, together with 1D NMR and 2D NMR spectroscopy, confirmed the successful synthesis of the investigated pyrazolopyrimidines. Among the synthesized compounds, 4a and 4b , bearing methoxy substituents, exhibited the strongest antioxidant activity and selective cytotoxicity toward MDA‐MB‐231 breast cancer cells (IC 50 = 9.82 and 8.64 μg/mL, respectively), along with insignificant impacts on the normal WI‐38 cells. Molecular docking verified strong binding interactions with the MDA‐MB‐231 receptor protein (PDB ID: 4GL7). Conclusion The present work highlights a greener and sustainable route for the synthesis of bioactive pyrazolopyrimidines using an efficient nanocatalyst with considerable potential for antioxidant and anticancer applications. © 2025 Society of Chemical Industry (SCI).