Structural Diversification of Thiadiazole and Oxadiazole-Based (R)-N-(1-(Naphthalen-1-yl)ethyl)benzamide Derivatives as Potential SARS-CoV-2 Papain-Like Protease Inhibitors for the Treatment of COVID-19: Insight from Computational Profiling

The papain-like protease (PLpro) of SARS-CoV-2 plays a key role in viral polyprotein processing and suppression of host innate response, making it valuable target for development of anti-viral drugs. However, the availability of potent small-molecule SARS-CoV-2 Papain-like Protease (PLpro) inhibitors remain limited. In the current study novel series of compounds based on (R)-N-(1-(naphthalen-1-yl)ethyl)benzamide bearing thiadiazole/oxadiazole (14a-14g & 15a-15g) scaffolds have been designed and synthesized as novel SARS-CoV-2 (PLpro) inhibitors. The synthesized compounds were characterized using 1 H NMR, 13 C NMR and HRMS and then evaluated for in vitro enzymatic inhibition against SARS-CoV-2 (PLpro). Several compounds demonstrated moderate to potent SARS-CoV-2 (PLpro) inhibition, with an IC 50 values in the range of 0.0460 ± 0.0028 μM to 20.13 ± 2.83 μM. The obtained results were compared to standard inhibitor GRL0617 (IC 50 = 2.4 ± 0.29 μM). Specifically, compounds 15c (IC 50 = 0.0460 ± 0.0028 μM), 14a (IC 50 = 0.2194 ± 0.019 μM), 14g (IC 50 = 0.2521 ± 0.033 μM), 14c (IC 50 = 0.4475 ± 0.063 μM) and 15a (IC 50 = 0.9161 ± 0.196 μM) were found to be more potent against SARS-CoVManuscript 2 (PLpro), even more active than standard inhibitor. Structure–activity relationship (SAR) evaluation shown that the inhibitory potency is mainly influenced by the substitution pattern of the aryl moiety attached to the thiadiazole/oxadiazole motif. The molecular docking study of most active compound 15c demonstrated favorable binding conformation within the SARS-CoV-2 (PLpro), highlighted by stable hydrogen bonding and hydrophobic interactions with key catalytic residues, thereby enhancing inhibitory potency. Additionally, DFT calculations and in silico ADMET analyses of potent compound 15c indicated favorable electronic behavior and provided preliminary insight into its pharmacokinetic and safety characteristics, thereby supporting its potential for further structural optimization. Altogether, these findings identify lead compound 15c as promising tool for further optimization and development of new and improved SARS-CoV-2 (PLpro) inhibitors for combating COVID-19.