Exploring chalcone analogues as potential SARS-CoV-2 inhibitors: insights from synthesis, crystal analysis, molecular dynamics simulations, docking and ADMET studies

Abstract Chalcone-based analogues have gained significant attention due to their promising inhibitory activity against multiple viral targets. To identify potential anti-SARS-CoV-2 drug candidates, we designed and synthesized novel chalcone analogues via the Claisen–Schmidt reaction, affording excellent product yields (87–94%). Compound 3c was crystallized by slow evaporation of an ethanolic solution at room temperature. X-ray diffraction analysis revealed that the compound crystallized in the monoclinic crystal system with P21/c space group. The crystallographic data uncovered crystal packing, bond lengths, bond angles and other key parameters. Docking studies revealed that the synthesized compounds 3(a–d) exhibited moderate binding affinities, with compound 3d showing the strongest affinity at −4.657 kcal mol−1. These values are less favourable than the reference inhibitors (−7.424 and −8.245 kcal mol−1 for the co-crystallized ligand and remdesivir, respectively), suggesting potential for further optimizations through medicinal chemistry approaches. The molecular dynamics simulations of the 3d complex demonstrated fluctuations within a satisfactory range (2.5–4.5 Å), as observed in the root mean square deviation plots at 100 ns. Furthermore, absorption, distribution, metabolism and excretion analysis indicated that all compounds displayed drug-like properties, with high gastrointestinal absorption, suggesting bioavailability. The present work provides a promising platform for further development of chalcone-based compounds as promising anti-SARS-CoV-2 agents.