Design, synthesis, and structural characterization of novel 4-aminoantipyrine derivatives: Experimental and computational insights via DFT and molecular docking

4-Aminoantipyrine (4-AAP) derivatives are of significant interest in medicinal chemistry because of their diverse therapeutic potentials. In this study, we report the synthesis of five novel 4-aminoantipyrine derivatives ( P1–P5 ). The synthetic approach involved the initial preparation of enaminone ( I1 ) via a solvent-free reaction of 4-aminoantipyrine with acetylacetone, followed by condensation with various primary amines or hydrazides in refluxing ethanol solution. The chemical structures of the prepared compounds were characterized using mass spectrometry, FT-IR, and NMR ( 1 H and 13 C) spectroscopy. Density functional theory (DFT) calculations were performed at the B3LYP/6-311++G (d,p) level to optimize the molecular geometries and evaluate the global reactivity properties. Computational analysis revealed that the planarity of the molecules was highly dependent on the substituents of the imine moiety, with compounds P1 , P4 , and P5 exhibiting near-planar geometries. Furthermore, molecular docking simulations were conducted against Human DNA Topoisomerase I (PDB: 1T8I) to assess the binding affinity and potential anticancer mechanisms of the derivatives. These results were complemented by ADMET and toxicity predictions using the Swiss ADME and ProTox-3.0 platforms to evaluate their pharmacokinetic profiles and drug-like properties. This integrated experimental and theoretical study highlights the potential of these new 4-AAP derivatives as scaffolds for the development of bioactive agents.