Repurposing 1,2,4-oxadiazoles as SARS-CoV-2 PLpro inhibitors and investigation of their possible viral entry blockade potential

Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary Antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like Protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 Plpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget Antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion^. The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 Plpro (IC₅₀₌7.197 μM) and spike protein RBD (IC₅₀ = 8.673 μM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC₅₀ = 51.78 μM) and LT-A549 (CC₅₀ = 45.77 μM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies.

1,2,4-Oxadiazole; PLpro; SARS-CoV-2; Spike RBD.