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Understanding the SARS‐CoV‐2 virus’ routes of infection, virus–host–protein interactions, and mechanisms of virus‐induced cytopathic effects will greatly aid in the discovery and design of new therapeutics to treat COVID‐19. Chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID‐19, have multiple cellular effects including alkalizing lysosomes and blocking autophagy as well as exhibiting dose‐limiting toxicities in patients. To identify an alternative lysosome‐based drug repurposing opportunity we evaluated additional lysosomotropic compounds . We found that six of these compounds blocked the cytopathic effect of SARS‐CoV‐2 in Vero E6 cells with half‐maximal effective concentration (EC50) values ranging from 2.0 to 13 μM and selectivity indices (SIs; SI = CC50/EC50) ranging from 1.5‐ to >10‐fold. We demonstrate how the compounds (1) blocked lysosome functioning and autophagy, (2) prevented pseudotyped particle entry, (3) increased lysosomal pH, and (4) that ROC‐325 reduced viral titers in the EpiAirway 3D tissue model. Consistent with these findings, the siRNA knockdown of ATP6V0D1 blocked the HCoV‐NL63 cytopathic effect in LLC‐MK2 cells. Moreover, an analysis of SARS‐CoV‐2 infected Vero E6 cell lysate revealed significant dysregulation of autophagy and lysosomal function, suggesting a contribution of the lysosome to the life cycle of SARS‐CoV‐2. Our findings support targeting the lysosome to combat SARS‐CoV‐2 infections and inhibitors of lysosomal function could become an important component of drug combination therapies aimed at improving treatment and outcomes for COVID‐19.

A novel Schiff base macrocyclic ligand was synthesized by the condensation of 4-(3,4-diaminophenyl)benzene-1,2-diamine with β-naphthol-1-aldehyde.Binuclear complexes were synthesized from this Schiff base by reaction with Cu (II), Ni (II), Ru (II), and Zn (II) metal salts. Square planar geometrical structures of Cu (II), Ni (II), and Ru (II) complexes were achieved by several physicochemical methods, namely UV-Vis, FT-IR, NMR, ESI-Mass, and thermogravimetric analysis, respectively. Density functional theory (DFT) calculations at the B3LYP/6-31G(d) level were carried out to gain an insight into the thermodynamic stability and biological accessibility of the complexes. Moreover, molecular docking analysis was done against a novel target protein PDB: 6M71 (SARS-CoV-2). Both the Schiff base ligand and metal complexes showed excellent interaction with protein receptor. All the metal complexes have the strong tendency to undergo intercalation mode of binding with CT DNA. All the in vivo and in vitro screening studies showed that the complexes exhibit higher activities than the free Schiff base.