Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus

• Published in: Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (13), p.3709-3712
• Main Authors: Mandadapu, Sivakoteswara Rao, Weerawarna, Pathum M., Prior, Allan M., Uy, Roxanne Adeline Z., Aravapalli, Sridhar, Alliston, Kevin R., Lushington, Gerald H., Kim, Yunjeong, Hua, Duy H., Chang, Kyeong-Ok, Groutas, William C.
• Format: Article
• Language: English
• Subjects: 3C and 3CL proteases; chemistry; Coronavirus; Coronavirus - enzymology; Dose-Response Relationship, Drug; Drug Design; Enterovirus; in vitro studies; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Macrocyclic inhibitors; Models, Molecular; Molecular Conformation; Norovirus; Norovirus - enzymology; Peptide Hydrolases - metabolism; Picornaviridae - enzymology; Picornavirus; Picornavirus-like supercluster pathogens; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; proteinases; SARS coronavirus; Severe acute respiratory syndrome coronavirus; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.05.021

The design, synthesis, and in vitro inhibitory activity of the first series of macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus, are reported. The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1μM, respectively.