Synthesis, computational studies and In Silico approaches of novel organophosphorus derivatives as anti-Alzheimer Agents

Abstract

• A facile synthesis of novel organophosphorus 3 and the tetraethyl 4-nitroalk-1-ene-2,3-diyldiphosphonate (TNDP) 4a-e . • A DFT study was carried for all compounds using the functional (B3LYP) and the 6–311+G(d,p) basis set. • The geometric parameters such as chemical hardness ( η ), chemical potential ( µ ), electrophilicity index ( ω) , chemical softness ( σ ) were calculated depending on the calculated HOMO-LUMO energies. • Molecular docking was performed to evaluate the antibacterial and anti-Alzheimer activities. A novel established of compounds as 1,2-oxaphosphol-3-ene 3 and tetraethyl 4-nitroalk-1-ene-2,3-diyldiphosphonate 4a-e were synthesized through the coupling reaction of phosphonoallyl bromide E -2 with triethyl ammonium formate (TEAF) and nitroalkane salts under basic conditions. The characterization of all compounds was skilled by NMR Spectroscopy and HRMS. Theoretical study of the components was studied using DFT calculations at B3LYP/6–311+G(d,p) levels. The Molecular electrostatic potential study revealed possible nucleophilic and electrophilic attack areas inside the phosphorus compounds. The calculation of energy gap was used to study the probability of charge transfer in the products. The biological activity of all molecules 3 and 4a-e was evaluated and indicated that diethyl (2‑hydroxy-2-oxido-2,5-dihydro-1,2-oxaphosphol-4-yl) phosphonate 3 as an antibacterial activity compared to the other molecules. Molecular docking was conducted to explore the interaction modes between the oxaphosphol-3-ene 3 and nitroalkene derivatives 4a-e with various proteins. The obtained results suggested the minimum binding affinity between the ligands and the target macromolecules, indicating their potential as membrane-permeable inhibitors.