Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising -anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies

Abstract

In this study, a library of phthalimide Schiff base linked to 1,4-disubstituted-1,2,3-triazoles was designed, synthesised, and characterised by different spectral analyses. All analogues have been introduced for in vitro assay of their antiviral activity against COVID-19 virus using Vero cell as incubator with different concentrations. The data revealed most of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with no or weak cytotoxic effect on Vero cells. Furthermore, in vitro assay was done against this enzyme for all analogues and the results showed two of them have IC50 data by 90 µM inhibitory activity. An extensive molecular docking simulation was run to analyse their antiviral mechanism that found the proper non-covalent interaction within the Mpro protease enzyme. Finally, we profiled two reversible inhibitors, COOH and F substituted analogues that might be promising drug candidates for further development have been discovered.

Keywords: 123-Triazole; COVID-19; Schiff bases; molecular docking; phtalamide.

Graphical abstract

Figure 1.

Used drugs for the treatment of SARS-CoV-2 infection.

Figure 2.

(A) docking pose of compound 11 in complex with M^pro (PBD ID 5R80) (left) and the 2D interaction map (right) showing the fundamental interactions of certain moieties in 11 with the protein; (B) The suggested modification aiming to improve its binding with the protein and enhance its anti-Covid activity.

Scheme 1.

Synthesis of phthalimide Schiff base with terminal alkyne tether 4.

Scheme 2.

Synthesis of 1,2,3-triazole-phthalimide hybrids with phenylacetamide tethers 6a-g.

Scheme 3.

Synthesis of 1,2,3-triazole-phthalimide hybrids bearing aromatic ring 8a-h.

Scheme 4.

Synthesis of 1,2,3-triazole-phthalimide hybrids bearing glycosyl moiety 10a-b.

Figure 3.

Dose starting from 10 uM of the tested compounds.

Figure 4.

Docked poses of M^pro protease (PDB ID: 5R80) complexed with Z18197050 and 6 g compound with 2D interaction map for 6 g (right) and 3D interaction map of both aligned compounds (left).