Design, Synthesis, DFT Study, Molecular Docking, and Molecular Dynamics of Novel α-Aminophosphonate Derivatives from Dehydroacetic Acid

Abstract

An efficient and facile protocol was developed for the synthesis of α-aminophosphonates via the Pudovik reaction under various catalysts FeCl3, AlCl3, ZnO, Cu2O, TiO2, HCl and H2SO4. Out of several candidate catalysts, FeCl3 is the most worked out catalyst, and as such, a maximum product formation was reported. This method proceeds under mild conditions, delivering α-aminophosphonate derivatives in high chemical yields. In this study, the performances of different DFT methods calculations were conducted using the B3LYP functional with a 6-311G(d,p) basis set to predict the molecular structural and electronic properties of the synthesized compounds. Frontier molecular orbitals (HOMO/LUMO) were calculated to identify charge transfer properties and predict structure-activity relationships. Additionally, silico pharmacokinetic and ADMET properties were assessed using SwissADME, confirming drug-likeness and favorable oral bioavailability based on Lipinski’s rule of five. Molecular docking studies were implemented to evaluate the binding affinity of the α-aminophosphonates with the Human TopoIIa ATPase/AMP-PNP (PDB ID: 1ZXM), revealing significant interactions comparable to known inhibitors, thereby supporting their potential anticancer activity. Finally, molecular dynamics simulation studies indicated stable bindings throughout the simulation. These results demonstrate the potential of α-aminophosphonates as promising therapeutic development candidates.