Synthesis, crystal structure, pharmacophore analysis and molecular docking of monoterpene-isatin conjugates as potential SARS-CoV-2 PLpro ligands with in vitro antiviral evaluation

Abstract

A series of novel conjugates combining monoterpenoid fragments (camphor, fenchone) with an isatin scaffold was designed as potential SARS-CoV-2 PLpro inhibitors. Molecular docking and pharmacophore analysis confirmed their ability to bind to the active site of PLpro. Single crystal of target compound 12 was grown, the structure was confirmed by X-ray diffraction. The structure was shown to be formed by chains of dimers: dimers from π-stacking interactions between isatin and dimers from N–H···O hydrogen bonds between acylhydrazone fragments.. Compound 10, a (-)-camphor derivative, exhibited moderate antiviral activity against both the Wuhan and the JN.1 variant of SARS-CoV-2 in Vero E6 cells, validating the computational predictions and highlighting the importance of stereochemistry for biological activity.