Towards potent Covid-19 spike protein inhibitors and catecholase activity agents: Synthesis, ADME-Tox analysis and molecular docking of new 1,2,4- triazole-based molecules

Abstract

AbstractThe discovery of new efficiency therapeutic agents that can block the adhesion of the transmembrane glycoprotein Spike (S-protein) to the human angiotensin-converting enzyme 2 (hACE2) receptor remains one of the most investigated strategies to fight against Covid-19 pandemic. In this context, new triazole derivatives have been synthesized through condensation reactions between (1H-1, 2, 4-triazol-1-yl)methanol and different secondary amines. Their chemical scaffolds were well illuminated by1H/13C/ COSY/ HSQC NMR, FT-IR and mass spectroscopies.In silicoinvestigations have been carried out. ADME-Tox screening revealed that the prepared compounds could serve as excellent oral candidate drugs with optimal pharmacokinetic proprieties and toxicological profiles. Molecular docking simulations against the isolated S-RBD protein and SARS-CoV-2-RBD- hACE2 complex showed that our compounds could form important hydrogen, hydrophobic and electrostatic interactions with some key residues that ensure the binding of the S-protein to its hACE2 receptor making them good candidate agents that can block or prevent the entry of SARS-CoV-2 virus in the host cell. Additionally, catecholase activity of the tridentate ligands have been studied. The obtained findings demonstrated that a systematic variation of the ligand substituent and metallic salts types, significantly influences the interaction of thein situcomplexes with catechol and hence the oxidase biomimetic catalytic activities. Complex L3/Cu(CH3COO)2was found to exhibit the highest activity towards oxidation of catechol to its corresponding quinone with a rate of 2.44 𝜇mol.l−1.min−1.