A novel pyrazole derivative as COVID-19 main protease inhibitor: Synthesis, quantum computational studies, pharmacokinetic properties, drug likeness, molecular docking and dynamics simulation; a CADD approach

Abstract

2-(3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-4H benzo[d][1,3]oxazin-4-one (2-BCBO) compound, was synthesized by the reaction of 3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in acetonitrile and methane sulfonyl chloride. The monoclinic crystal structure in C2/c space group of the compound was unveiled through single-crystal X-ray diffraction studies. A prediction model was employed to investigate the influence of intermolecular contacts on molecular packing in the crystalline phase. The model incorporated both Hirshfeld surface and 2D fingerprint models to gain a comprehensive understanding of the strength of these contacts. The calculation of the total interaction energy was conducted by utilizing the three-dimensional molecular energy frameworks and further, employed density functional theory to examine molecular orbital characteristics and key factors associated with chemical reactivity. The application of topological analysis techniques, such as QTAIM and NCI, provided further insight regarding the attraction and repulsive interactions shown by the molecule. The pharmacokinetic properties of the 2-BCBO molecule have also been examined using ADMET analysis, which is important in drug discovery and development. In addition, the molecular docking study to determine the inhibitory effect of the investigated ligand on the main protease of new coronavirus (COVID-19), followed by molecular dynamics simulations, and it is found that both the results are in good agreement. The 2-BCBO could be accepted as a lead molecule to treat the coronavirus.