Synthesis, Cytotoxicity, Antioxidant Activity, DFT Calculations, and Docking Studies of New Pyridine-Malonate Derivatives as Potential Anticancer Agents

A series of new pyridine-malonate derivatives were synthesized and fully characterized by ¹HNMR, ¹³CNMR, FTIR, and elemental analysis. Their molecular geometry and chemical reactivity have been investigated using DFT calculations. The cytotoxicity of all synthesized compounds was assessed against two human cancer cell lines (MCF-7 and A-2780) using the MTT assay. Among them, compounds 2a, 2c, 2e, and 2g showed comparable or more potent cytotoxicity toward the MCF-7 cells than the reference drug docetaxel (IC₅₀ = 0.34–0.47 vs. 0.50 µM). In contrast, only compound 2g showed more potent cytotoxicity against the A-2780 cell line compared to the standard (IC₅₀ = 0.36 vs. 0.42 µM). The docking study revealed a good affinity for the active site of the human topoisomerase-IIβ enzyme, which may explain the promising cytotoxicity of these classes of molecules. The radical scavenging activity of the respective compounds was studied using DPPH radical scavenging assay and it was found that most of the compounds are moderate DPPH radical scavengers compared to the standard drugs BHA and BHT.