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  2. 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

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

  • J Mol Struct. 2023 Aug 5:1285:135525. doi: 10.1016/j.molstruc.2023.135525.
Mohamed Azzouzi 1 Zainab El Ouafi 2 Omar Azougagh 1 Walid Daoudi 1 Hassan Ghazal 2 3 Soufian El Barkany 1 Rfaki Abderrazak 4 Stéphane Mazières 5 Abdelmalik El Aatiaoui 1 Adyl Oussaid 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Chemistry, Materials and Environment (LCM2E), Department of Chemistry, Multidisciplinary Faculty of Nador, University Mohamed I, Nador 60700, Morocco.
  • 2 Laboratory of Genomics and Bioinformatics, School of Pharmacy, Mohammed VI University of Health Sciences Casablanca, Casablanca, Morocco.
  • 3 Electronic Systems, Sensors and Nanobiotechnologies (E2SN), École Nationale Supérieure des Arts et Métiers (ENSAM), Mohammed V University, Rabat, Morocco.
  • 4 National Center for Scientific and Technical Research (CNRST), Rabat, Morocco.
  • 5 Laboratory of IMRCP, University Paul Sabatier, CNRS UMR 5623, 118 route de Narbonne, Toulouse 31062, France.
Abstract

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.

Keywords

ADMET; DFT calculations; Drug-likeness; Imidazo[1,2-a]pyrimidine; Molecular docking; SARS-COV-2; Schiff base.

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