In silico assessment and sonochemical synthesis of 2-alkynyl 3-chloropyrazines as prospective ligands for SARS-CoV-2

Abstract

The recent global pandemic caused by COVID-19 has triggered an intense effort worldwide towards the development of an effective cure for this disease. In our effort we have explored the 2-alkynyl substituted 3-chloropyrazine framework as a potential template for the design of molecules for this purpose. Our strategy was supported by the in silico studies of representative compounds to assess their binding affinities via docking into the N-terminal RNA-binding domain (NTD) of N-protein of SARS-CoV-2. Thus we created a small library of molecules based on the aforementioned template via an environmentally safer method that involved the rapid synthesis of 2-alkynyl 3-chloropyrazine derivatives under Cu-catalysis assisted by ultrasound. The reactions proceeded via the coupling of 2,3-dichloropyrazine with commercially available terminal alkynes in the presence of CuI, PPh3 and K2CO3 in PEG-400. Further molecular modelling studies helped in establishing a virtual SAR (Structure Activity Relationship) within the series and identification of three potential hits. The desirable ADME was also predicted for these three molecules suggesting their prospective medicinal value.