Novel compounds with dual inhibition activity against SARS-CoV-2 critical enzymes RdRp and human TMPRSS2

COVID-19 caused major worldwide problems. The spread of variants and limited treatment encouraged the design of novel anti-SARS-CoV-2 compounds. A series of compounds RH1-23 were designed to dually target RNA-dependent RNA polymerase (RdRp) and transmembrane serine protease 2 (TMPRSS2). Compared to remdesivir, in vitro screening indicated the highest selectivity and potent activity of RH11–13 with half maximum inhibitory concentration (IC50) 3.9, 5.7, and 19.72 nM, respectively. RH11–12 showed superior inhibition activity against TMPRSS2 and RdRP with IC50 (1.7 and 4.2), and (6.1 and 4.42) nM, respectively. WaterMap analysis and molecular dynamics studies demonstrated the superior enzyme binding activity of RH11 and RH12. On Vero-E6 cells, RH11 and RH12 significantly inhibited the viral replication with 66 % and 63.2 %, and viral adsorption with 44 % and 65 %, alongside virucidal effect with 51.40 % and 90.5 %, respectively. Furthermore, the potent activity of RH12 was tested on TMPRSS2-expressing cells (Calu-3) compared to camostat. RH12 exhibited selectivity index (26.05) similar to camostat (28.01) and comparable to its SI on Vero-E6 cells (22.6). RH12 demonstrated also a significant inhibition of the viral adsorption on Calu-3 cells with 60 % inhibition at 30 nM. The designed compounds exhibited good physiochemical properties. These findings indicate a broad-spectrum antiviral efficacy of the designed compounds, particularly RH12, with a promise for further development. [Display omitted] •A series of compounds were designed to inhibit RdRp and TMPRSS2, critical proteins in COVID-19.•The designed compounds exhibited potent selectivity compared to remdesivir.•RH11 and RH12 showed significant inhibition of viral replication and adsorption with a virucidal effect.•The designed compounds exhibited excellent molecular binding and physicochemical properties.