Beclabuvir hydrochloride

New pseudonucleosides containing cyclic sulfamide moiety and sulfamoyl β-D-glucosamine derivative are described. These pseudonucleosides are synthesized in good yields starting from chlorosulfonyl isocyanate and β-D-glucosamine hydrochloride in five steps; (protection, acetylation, removal of the Boc group, sulfamoylation, and cyclization). Further, novel glycosylated sulfamoyloxazolidin-2-one is prepared in three steps; carbamoylation, sulfamoylation, and intramolecular cyclization. The structures of the synthesized compounds were confirmed by usual spectroscopic and spectrometric methods NMR, IR, MS, and EA. Interesting molecular docking of the prepared pseudonucleosides and (Beclabuvir, Remdesivir) drugs with SARS-CoV-2/M^pro (PDB:5R80) was conducted using the same parameters for a fair comparison. A low binding affinity of the synthesized compounds compared to the Beclabuvir and other analysis showed that pseudonucleosides have the ability to inhibit SARS-CoV-2. After the motivating results of molecular docking study, the complex between the SARS-CoV-2 M^pro and compound 7 was subjected to 100 ns molecular dynamics (MD) simulation using Desmond module of Schrodinger suite, during which the receptor-ligand complex showed substantial stability after 10 ns of MD simulation. Also, we studied the prediction of absorption, distribution, properties of metabolism, excretion, and toxicity (ADMET) of the synthesized compounds.Communicated by Ramaswamy H. Sarma.

A new coronavirus strain called as SARS-CoV-2 has emerged from Wuhan, China in late 2019 and it caused a worldwide pandemic in a few months. After the Second World War, it is the biggest calamity observed as there is no specific US Food and Drugs Administration (USFDA) approved drug or vaccine available globally for the treatment. Several clinical trials are ongoing for therapeutic alternatives, however with little success rate. Considering that the time is crucial, the drug repurposing and data obtained from in silico models are one of the most important approaches to identify possible lead inhibitors against SARS-CoV-2. More recently, the Direct Acting Antivirals (DAAs) are emerged as the most promising drugs to control viral infection. The Main Protease (Mpro), a key enzyme in the SARS-CoV-2 replication cycle, is found close homolog to the Hepatitis C Virus (HCV) protease and could be susceptible of blocking its activity by DAAs. In the current study, the DAAs were investigated as antivirals using structure based computational approach against Mpro of SARS-CoV-2 to propose them as new therapeutics. In total, 20 DAAs of HCV, including a reference compound O6K were docked against Mpro. The docked structures were examined and resulted in the identification of six highly promising DAAs i.e. beclabuvir, elbasvir, paritaprevir, grazoprevir, simeprevir, and asunapevir exhibiting high theoretical binding affinity to Mpro from SARS-CoV-2 in comparison to other DAAs. Furthermore, the post docking analysis revealed that Cys145, Glu166, His163, Thr26, His41, and Met165 played potential role for the binding of these DAAs inside binding site of Mpro. Furthermore, the correlation between binding energies were found in accord with the results from the reported IC₅₀s for some DAAs. Overall, the current study provides insight to combat COVID-19 using FDA-approved DAAs as repurposed drugs.