In the present research work, we report the synthesis and characterization of novel pyrazole derivative obtained by the condensation reaction of 4-nitro benzaldehyde group with one equivalent of the 2-amino pyrazole yielding 4-nitro-N-1H-pyrazol-3-ylbenzamide with high yield. The two symmetry-independent molecules (molecule A and molecule B) differ about the central C-N bond, with the dihedral angles between the pyrazole ring system and the nitrobenzene ring being 13.90° and 18.64°, respectively. By optimizing the symmetry-independent dimer molecules, the rotational barrier between the conformers is found to be within the 2.5-5.5 kcal/mol range. QTAIM and RDG based NCI isosurface revealed the presence of strong N-H…N and C-H…O hydrogen bonds which stabilize the two independent centrosymmetric inversion-related dimers. Further, weak and short directional interactions such as C-H…N, H…H and C-H…π were also analyzed systematically using various topological parameters. The compound is found to adhere to the Lipinski's rule of five and exhibit good pharmacokinetic properties. The results of molecular docking studies performed against SARS-CoV-2 virus main protease (PDB IDs: 6LU7, 6W9C and 6WQF) revealed that the compound showed better docking scores. Molecular docking studies verified the inhibition activity of the synthesized novel compound. Finally, the binding free energy and contributed energies were calculated using MM-GBSA method. The 6LU7-ligand complex showed highest binding free energy and among all other interactions, the contributions of the covalent binding and van der Waals energy are found to be significant.Communicated by Ramaswamy H. Sarma.
Keywords: ADMET analysis; DFT; NCI; Pyrazole derivative; QTAIM; crystal structure analysis; molecular docking; molecular dynamics and MM-GBSA.