Synthesis of Dihydrobenzofuro[3,2‐b]chromenes as a potential 3CLpro inhibitors of SARS‐CoV‐2: A molecular docking and dynamics simulation study

The recent emergence of pandemic of coronavirus caused by SARS-CoV-2 has raised significant global health concerns. There is no specific therapeutics currently available to combat against this deadly infection. The enzyme 3-chymotrypsin-like cysteine protease (3CLpro) is known to be essential for viral life cycle as it controls the coronavirus replication, thus could be a potential drug target. Here, we explored the potential of fused flavonoids as anti-CLpro inhibitors. Fused flavonoids are unexplored for their potential bioactivities due to their low natural occurrences. Their synthetic congeners are also rare due to unavailability of general synthetic methodology. Here we designed a simple strategy to synthesize 5a,10a-dihydro-11H-benzofuro[3,2-b]chromene skeleton and it's four novel derivatives. Our structural bioinformatics study clearly shows excellent potential of the synthesized compounds in comparison to experimentally validated inhibitor N3. Moreover, in-silico ADMET study displays drugability and extremely low level of toxicity of the synthesized molecules. Further, the molecular dynamic approach was implemented to study the change in dynamicity after the compounds bind to the protein. In summary, we anticipate that the currently synthesized molecules could not only be a potential set of inhibitors towards against CLpro but also the insights acquired would be instrumental in further developing novel natural flavonoid based anti-COVID therapeutic spectrums.