The COVID-19 pandemic has underscored the urgent need for antiviral agents capable of targeting a broad range of coronaviruses, including emerging variants of SARS-CoV-2. While vaccines have been pivotal, the search for drugs that can prevent viral entry into host cells remains crucial, especially against evolving viral forms and other coronaviruses. In this study, we investigated natural products as a source of antiviral agents, focusing on their potential to block the spike protein's receptor-binding domain (RBD). Utilizing a library of over 210,000 natural product-based compounds from the ZINC database, we employed a Snakemake workflow to screen for inhibitors against RBDs of SARS-CoV-2, its variants, SARS-CoV, and MERS-CoV. Among top N-heterocyclic candidates from virtual screening we found that one compound, i.e ., ((2  R ,8 S )-6-(1-benzylpiperidin-4-yl)-2-naphthalen-1-yl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15 tetraene-4,7-dione), inhibited SARS-CoV-2 pseudovirus and live virus entry in HEK-ACE2 and Vero E6 host cells at low micromolar IC ₅₀ values. Cell viability assays showed that this compound exerted low cytotoxicity towards HEK-ACE2 while it was not toxic against Vero E6 and MRC5 cell lines. Microscale thermophoresis revealed that this compound strongly bound to the RBDs of SARS-CoV-2, SARS-CoV-2 XBB, SARS-CoV, MERS-CoV, and HCoV-HKU1, with their K _d values increasing as sequence similarity decreased. Molecular docking studies indicated this active compound binds to the SARS-CoV-2 spike protein RBD and interacts with hotspot amino acid residues required for the RBD-ACE2 interaction and cellular infection. These findings show that this diketopiperazine/piperidine-type alkaloid can be considered for further development as a potential pan-coronavirus entry inhibitor.