Synthesis and in Silico Investigation of Organoselenium-Clubbed Schiff Bases as Potential Mpro Inhibitors for the SARS-CoV-2 Replication.

Since the first report of the organoselenium compound, ebselen, as a potent inhibitor of the SARS-CoV-2 Mpro main protease by Z. Jin et al. (Nature, 2020), different OSe analogs have been developed and evaluated for their anti-COVID-19 activities. Herein, organoselenium-clubbed Schiff bases were synthesized in good yields (up to 87%) and characterized using different spectroscopic techniques. Their geometries were studied by DFT using the B3LYP/6-311 (d, p) approach. Ten FDA-approved drugs targeting COVID-19 were used as model pharmacophores to interpret the binding requirements of COVID-19 inhibitors. The antiviral efficiency of the novel organoselenium compounds was assessed by molecular docking against the 6LU7 protein to investigate their possible interactions. Our results showed that the COVID-19 primary protease bound to organoselenium ligands with high binding energy scores ranging from -8.19 to -7.33 Kcal/mol for 4c and 4a to -6.10 to -6.20 Kcal/mol for 6b and 6a. Furthermore, the docking data showed that 4c and 4a are good Mpro inhibitors. Moreover, the drug-likeness studies, including Lipinski's rule and ADMET properties, were also assessed. Interestingly, the organoselenium candidates manifested solid pharmacokinetic qualities in the ADMET studies. Overall, the results demonstrated that the organoselenium-based Schiff bases might serve as possible drugs for the COVID-19 epidemic.

New Dual Inhibitors of SARS-CoV-2 Based on Metal Complexes with Schiff-Base 4-Chloro-3-Methyl Phenyl Hydrazine: Synthesis, DFT, Antibacterial Properties and Molecular Docking Studies

This paper explores a dual inhibition of main protease (Mpro) and nonstructural protein 10/nonstructural protein 16 (NSP16) methyltransferase complex as the key targets for COVID-19 therapy. These are based on the new Schiff-base ligand that was obtained from the condensation of (4-chloro-3-methyl phenyl) hydrazine with 2-pyridine-carboxaldehyde and its novel Schiff-base metal complexes. These include Ni(II), Pd(II), Pt(II), Zn(II), and Hg(II). The newly synthesized compounds have been characterized using FT-IR, 1H NMR, 13C NMR, and elemental analysis. The results suggested that the Schiff-base ligand is coordinated as a bidentate ligand through the nitrogen atoms of the azomethine group and pyridyl ring. In addition, the biological activity of the prepared complexes was examined against Pseudomonas aeruginosa and Staphylococcus aureus, and the results showed that the Zn(II) complex has the highest activity compared with other compounds. The active sites were found by looking at the molecular electrostatic potential (MEP) maps of the above ligands and complexes.. The activity of the compound and its Ni(II) and Zn(II) complexes against Mpro and NSP10/ NSP16 was investigated using a molecular docking approach. They showed excellent binding energies ranging from -5.9 to -7.2 kcal/mol and -5.8 to -7.2 for Mpro and NSP16, respectively. All conformers of the metal complexes were docked with the active site of the NSP16 receptor, showing a binding affinity of 100%. According to our knowledge, this was the first report of these metal complexes as dual inhibitors for Mpro and NSP16 of SARS-CoV-2.