SARS-CoV-2 Papain-Like Protease Inhibitors Based on Naphthalen-1-ylethanamine and Halogenated Benzene Moieties

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative virus of COVID-19, remains a worldwide health threat. SARS-CoV-2 possesses two types of proteases: a main protease (Mpro, 3C-like) and a papain-like protease (PLpro). These proteases cleave two translated nonstructural proteins, pp1a and pp1ab, into viral functional proteins. In the present study, we developed new inhibitors targeting the PLpro of SARS-CoV-2 based on GRL-0048 (2) as a lead compound. Structure–activity relationship (SAR) researches on GRL-0048 (2) led to the finding of compound 9r, which showed significantly enhanced inhibitory activity against PLpro. This enhancement was accomplished by the introduction of a halogenated aromatic carbonyl moiety into the parent structure of GRL-0048 (2).