Design, synthesis, and computational studies of novel imidazo[1,2-a]pyrimidine derivatives as potential dual inhibitors of hACE2 and spike protein for blocking SARS-CoV-2 cell entry.

• New imidazo[1, 2- a ]pyrimidine Schiff-bases derivatives have been synthesized. • Spectroscopic characterization was performed with 1H, 13C NMR, LC-MS, and FT-IR analyses. • The DFT studies, FMO, MEP, QTAIM and RDG analysis were done. • Molecular docking studies targeting the h ACE2 and the Spike, key entrance proteins of SARS-CoV-2 have been performed. • In silico ADMET and drug-likeness analysis were investigated. • This study may contribute to the ongoing efforts to develop effective treatments against SARS-CoV-2 or the upcoming variants. In the present work, a new series of imidazo[1,2- a ]pyrimidine Schiff base derivatives have been obtained using an easy and conventional synthetic route. The synthesized compounds were spectroscopically characterized using 1H, 13C NMR, LC-MS(ESI), and FT-IR techniques. Green metric calculations indicate adherence to several green chemistry principles. The energy of Frontier Molecular Orbitals (FMO), Molecular Electrostatic Potential (MEP), Quantum Theory of Atoms in Molecules (QTAIM), and Reduced Density Gradient (RDG) were determined by the Density Functional Theory (DFT) method at B3LYP/6–31 G (d, p) as the basis set. Moreover, molecular docking studies targeting the human ACE2 and the spike, key entrance proteins of the severe acute respiratory syndrome coronavirus-2 were carried out along with hACE2 natural ligand Angiotensin II, the MLN-4760 inhibitor as well as the Cannabidiolic Acid CBDA which has been demonstrated to bind to the spike protein and block cell entry. The molecular modeling results showed auspicious results in terms of binding affinity as the top-scoring compound exhibited a remarkable affinity (-9.1 and -7.3 kcal/mol) to the ACE2 and spike protein respectively compared to CBDA (-5.7 kcal/mol), the MLN-4760 inhibitor (-7.3 kcal/mol), and angiotensin II (-9.2 kcal/mol). These findings suggest that the synthesized compounds may potentially act as effective entrance inhibitors, preventing the SARS-CoV-2 infection of human cells. Furthermore, in silico, ADMET, and drug-likeness prediction expressed promising drug-like characteristics. [Display omitted] [ABSTRACT FROM AUTHOR]