Synthesis, Biological Evaluation and Molecular Modeling of novel series of 1,2,3-triazoles as potential anti-coronavirus agents

KARYPIDOU, KONSTANTINA; RIBONE, S. R.; QUEVEDO, M. A.; PANNECOUQUE, C.; DEHAEN, W.

Simposio; V Symposium of Medicinal Chemistry Young Researchers; 2018

Sociedad Española de Química Terapéutica

Coronaviruses are single-stranded RNA viruses associated with mild to severe respiratory syndrome (SARS-CoV).[1]To date there are no approved antiviral drugs used for the prevention and treatment of SARS-like coronaviruses making the development of an effective antiviral agent an imperative need.[2]The 3-chymotrypsin-like protease (3CLpro), also referred to as Main protease (Mpro) is essential to the viral replication inside the host cell,making it an attractive target for further development of novel inhibitors.[3] Potential antiviral agents are classified in peptidic and small molecule-based inhibitors.Reports on non-peptidic inhibitors highlight the presence of triazole motif as it forms key interactions with the catalytic dyad of the 3CLpro active site.[4] Considering our interest in the chemistry of 1,2,3-triazole bioactive molecules and their interesting binding mode, we generated a novel library of fused 1,2,3-triazoles based on a metal-free multicomponent reaction developed within our group starting from readily available enolizable carbonyl compounds, primary amines and 4-nitrophenyl azide [Figure 1].[5]Further, the synthesized derivatives were analyzed for their antiviral properties and studied based on different molecular modelling strategies (molecular docking, molecular dynamics and free-energy of binding analysis) in order to identify key intermolecular interactions with the 3CLpro.