Abstract

Background: Significant research efforts have been directed towards developing systems for enhancing the intracellular delivery of phosphate-substituted compounds, such as biologically active peptides and nucleotides. Phosphoramidates (P-N) are organophosphorus structures containing a single covalent bond between the P(V) and N(III) atoms. Three types of phosphoroamidates are discovered. Organophosphorus compounds, defined as (RO)2P(O)NR’2 (R, R’ = H, alkyl, aryl, heteroaryl), is a stable phosphoryl bond (P=O). Novel phosphoramidate derivatives of hydroxy functional or amino functional compounds include peptides, peptidomimetics and nucleotide analogs. The compounds enable enhanced intracellular delivery of drugs as their corresponding phosphate esters or amides. phosphoramidates exhibit antiproliferative activity and could be used for the treatment of cancers. Phosphoramidates exhibit potential applications in the field of biomedicine as antiviral, anti-HIV, antimalarial and anticancer agents.

Objective: A computer-aided investigation compared these new compounds to Remdesivir, assessing potential pharmacological properties.

Methods: An efficient microwave method was used to synthesize novel N-arylphosphoramidates from commercially available nitroarenes using trialkyl phosphites.

Results: Novel N-arylphosphoramidates are prepared with good yields and reduced reaction times. NMR spectroscopy (HH-COSY, HSQC, HMBC) elucidated their structures.

Conclusion: A practical reductive domino reaction involving a trialkyl phosphite under microwave irradiation has been developed to convert nitroarenes into dialkyl N-arylphosphoramidates. The comparative study conducted in this research effectively ranked compounds 5a-o concerning approved medications (Remdesivir), providing a solid foundation for further investigation. Molecular docking analysis of our 15 ligands and Remdesivir revealed several similarities. This indicates that Remdesivir, an approved drug, and our ligands have comparable binding affinities for the primary protease (PDB code 7BQY). Such insights encourage us for further exploration and optimization of their potential therapeutic applications as COVID-19 inhibitors. Molecular docking studies examined these compounds as COVID-19 inhibitors based on their interactions and binding affinities for the SARS-CoV-2 main protease (PDB code 7BQY).

Keywords: Microwaves, COVID-19, domino reactions, phosphoramidates, deoxygenation, antisense agents, structural adaptability.