A Facile Synthesis of 3-Substituted Coumarins and Investigation of Their 3CLpro Inhibition Activity Against SARS-CoV-2.

Abstract

The major threat to public health due to the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been recognised as a global issue. The increase in morbidity is primarily due to the lack of SARS-CoV-2 specific drugs. One of the major strategies to combat this threat is to deactivate the enzymes responsible for the replication of corona virus. To this end, 3-arylidene/3-hydroxycoumarin induced deactivation of 3-chymotrypsin like protease (3CLpro) enzyme, which takes the pivotal role in the replication and maturation, was investigated. For ready availability of the compounds for the above investigation, we have developed a user-friendly protocol for the synthesis 3-hydroxycoumarin derivatives from cheap and readily available starting materials in two steps; i) Bronsted acid catalysed Friedel-Crafts alkylation of phenols with Morita-Baylis-Hillman adducts followed by intramolecular lactonization to trans-3-arylidenechroman-2-ones in one-pot and ii) ozonolysis in reasonably good yields. Pharmacokinetic assessments of coumarin derivatives revealed drug-like characteristics with moderate or low toxicity values. Notably, these hydroxycoumarins exhibited enhanced binding affinity against the 3CL protease of SARS-CoV-2, fitting well into the binding pocket akin to the previously studied inhibitor N3. Furthermore, a molecular dynamics study elucidated the dynamic behaviour of these small molecules when bound to the protein, showcasing intriguing complexities within the active site. Despite backbone variations and residual fluctuations, compounds 3 d-f and 6 a exhibited a consistent behaviour, instilling confidence in the therapeutic potential of these coumarins for combating SARS-CoV-2.