The papain-like protease (PLpro) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) plays a key role in viral polyprotein processing and suppression of host innate response, making it a valuable target for the development of anti-viral drugs. However, the availability of potent small-molecule inhibitors of PL pro remains limited. The current study was designed to synthesize novel indole-tagged thia/oxadiazole scaffolds (10–23) and their inhibition profile against PL pro was tested, with GRL0617 used as a reference inhibitor. The evaluation revealed a broad spectrum of inhibitory potency, with IC 50 values ranging from 0.7934 μM to 23.79 μM. Remarkably, compounds 13 (IC 50 = 0.7934 μM), 11 (IC 50 = 1.118 μM), and 18 (IC 50 = 1.446 μM) demonstrated superior inhibitory potency relative to the reference inhibitor GRL0617 (IC.. = 2.40 μM). Based on structure-activity relationship (SAR) investigations, the alterations to the aryl ring substituents attached to the thia/oxadiazole scaffold were identified to be the key factor for modulating inhibitory potency. The molecular docking study of the most active compound 13 demonstrated a favorable binding conformation within the PL pro , highlighted by stable hydrogen bonding and hydrophobic interactions with key catalytic residues, thereby enhancing inhibitory potency. Additionally, DFT calculations and ADMET analyses of potent compound 13 showed favorable electronic properties and suitable pharmacokinetic properties, supporting its potential for further optimization. Altogether, these findings identify compound 13 as a potent early-stage enzymatic hit that provides a valuable starting point for further structural optimization toward the development of improved SARS-CoV-2 PL pro inhibitors.
Alwethaynani et al. (Fri,) studied this question.