Design, Synthesis, and Biological Evaluation of 1,2,4-Oxadiazole Derivatives Containing an Aryl Carboxylic Acid Moiety as Potent Sarbecovirus Papain-like Protease Inhibitors.

Papain-like protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds and , which had PLpro inhibition activity (IC = 1.8 and 1.0 μM) and antiviral activity against SARS-CoV-2 (EC = 5.4 and 4.3 μM), exhibited good metabolic stability ( > 93.2 min) and higher plasma exposure (AUC = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound with moderate oral bioavailability of 39.1% and potent antiviral activity is worthy of further studies . Our findings provide a new insight for the discovery of antiviral agents targeting PLpro.