Structural and Molecular Packing study of Three New Amidophosphoric Acid Esters and Assessment of Their Inhibiting Activity Against SARS‐CoV‐2 by Molecular Docking

Abstract

Three new compounds of amidophosphoric acid esters with a [OCH2C(CH3)2CH2O]P(O)[X] segment (where X=cyclopentylamido (1), 2‐aminopyridinyl (2) and pyrrolidinyl (3)) were synthesized and studied using FT‐IR and 31P/13C/1H NMR spectroscopies and single‐crystal X‐ray diffraction analysis. The compounds crystallize in the triclinic space groups Ptrue1‾ for 1 and 3 and in the orthorhombic space group Pca21 for 2, where the asymmetric unit consists of three symmetrically‐independent molecules for 1 and one molecule for 2 and 3. The intermolecular interactions and supramolecular assemblies are assessed by Hirshfeld surface analysis and enrichment ratios. The results reveal that the substituent effect plays an important role in directing the supramolecular structures. The presence of the aromatic substituent aminopyridine in 2 providing the C−H…π interactions leads to a larger variety in interactions including H…H, H…O/O…H, H…C/C…H and H…N/N…H contacts, whereas the packings of the compounds 1 and 3 bearing aliphatic substituents only include H…H and H…O/O…H contacts. The enrichment ratios affirm the importance of O…H/H…O contacts reflecting the hydrogen bond N−H…O interactions to be the enriched contacts. Compounds 1–3 were also investigated along with five similar reported structures with a [OCH2C(CH3)2CH2O]P(O) segment for their inhibitory behavior against SARS‐CoV‐2. The molecular docking results illustrate that the presence of the aromatic amido substituent versus the aliphatic type provides a more favorable condition for their biological activities.

Structural, Hirshfeld surface and molecular docking studies of a new organotin(IV)-phosphoric triamide complex and an amidophosphoric acid ester proposed as possible SARS-CoV-2 and Monkeypox inhibitors

“…In this esteric ring, the P═O bond is located in a position intermediate between equatorial and axial (with angles O P O –P−O estric = 113.68 (7)° and 114.39 (7)°, O P O –P–N = 115.15 (8)° and O estric −P–N = 105.43 (9)° and 104.30 (8)°). Such an intermediate position of the P═O bond has also been observed for similar amidophosphoric acid esters with a tertiary mine [ 27 ].…”

“…For 2 , the P═O, P–O and P–N bond lengths and O═P–N, O═P–O and O–P–N angles are similar to related compounds [ 27 , 51 ] ( Table S1 ). The tertiary amine N5 of this compound has a sp 2 hybridization and a planar configuration reflected in the sum of the surrounding angles (∠P–N–C + ∠P–N–C + ∠C–N–C) about 360° (360.0 (16)°).…”

“…Such interactions by helping the phosphoryl group are not possible for the complex 1 , where the P═O group has been coordinated to the tin metal center as Sn⋯O═P. Furthermore, recently we have carried out the molecular docking study on the different families of phosphoramides (phosphoric triamides [ 17 , 28 ], amidophosphoric acid esters [ 27 ] and some of phosphoric triamide Co 2+ and Cu 2+ complexes [ 19 ]) to evaluate their inhibitory activity against M Pro of SARS-CoV-2. The results of these studies show the negative binding energies in the range −4.7 to −6.9 kcal/mol for the ligand–protein interactions suggested as anti-coronavirus.…”

“…For this reason computer-aided drug discovery is being widely utilized to evaluate the potential of a compound as a drug to inhibit the disease-causing organisms, and molecular docking simulations in particular accelerates the choice of potential drugs for clinical trials [ [22] , [23] , [24] , [25] ]. In the case of phosphoramide compounds, some reports suggest them as possible inhibitors against SARS-CoV-2 by molecular docking studies that evaluate the binding interactions between the target protein of coronavirus and the tested drug compound [ [26] , [27] , [28] ].…”

Influence of N-protonation on electronic properties of acridine derivatives by quantum crystallography

“…The previously mentioned papers focus on structural and biochemical studies on compounds with potential pharmaceutical properties including anticancer 41 and antiviral activities. 42 In one study dedicated to protein–ligand interactions, it was found that ED polarization of the ligand molecule in the protein binding pocket could be used to predict the electrostatic features of the binding itself. However, these experimental results are difficult to interpret.…”