Palladium(II) aminoadamantane complexes: a promising approach to impair SARS-CoV-2 infection

The rapid geographic spread of SARS-CoV-2 infection, the high genetic variability resulting in the emergence of new variants, and the increase in post-COVID syndrome justify the discovery of new molecules that can abrogate viral infection. The aminoadamantanes amantadine (atd), memantine (mtn), and rimantadine (rtd) are commercial drugs used in the clinical treatment of Alzheimer disease and Influenza A virus infection and therefore are attractive candidates for synthesis of coordination compounds to increase their biological activity. Here, we screened atd, rtd, and mtn, together with palladium (II) [Pd(II)] and their respective metal complexes Pd-atd, Pd-mtn, and Pd-rtd, for activity against SARS-CoV-2 infection. This analysis demonstrated that the complexes Pd-atd, Pd-mtn, and Pd-rtd had antiviral activity with selectivity indices of 14.2, 36.2, and 23.5, respectively. Further assays were conducted, and all Pd(II) complexes strongly inhibited >75% of SARS-CoV-2 entry. Additionally, the Pd(II) complexes were able to inhibit the Omicron (BA.2) variant, with Pd-rtd also being able to inhibit cell-to-cell spread. Pd-atd significantly inhibited all stages of the replicative cycle investigated here, showing multiple effects on virus infection. The coordination with Pd(II) resulted in more active compounds with different mechanisms of action. Resistance-associated mutations in Spike, nsp1, and nsp3 are consistent with the hypothesis that the antiviral activity of the Pd(II) complexes involves different protein interactions. The obtained results highlight the synthesis of promising Pd(II) metallodrugs with potential application for the treatment of COVID-19 infections.