In-Silico Guided Design, Synthesis and Structure Activity Relationship Studies of Quinoline-Based Scaffolds as Novel SARS-CoV2- Main Protease Inhibitors: Insights into Experimental and Computational Profiling

Abnormal protease activity plays a crucial role in replication and survival of SARS-CoV-2, the causative agent of COVID-19. The main protease has therefore emerged as a vital therapeutic target in the discovery of antiviral drugs. In this study, a novel series of Quinoline-based scaffolds were synthesized via a multi-step sequence. The novelty of this work lies in the development of a quinoline-based molecular framework specifically tailored for Mpro inhibition, combined with a comprehensive structure–activity relationship (SAR) investigation integrating both experimental and computational approaches. The synthesized molecules were structurally confirmed by 1 H NMR, [Formula: see text]C NMR and HRMS analysis. The compounds were evaluated for their inhibitory activity against SARS-CoV-2 and several derivatives demonstrated promising potency. Particularly, compounds 9a (IC[Formula: see text] 63.3 ± 8.7 nM), 9 g (IC[Formula: see text] 67.8 ± 6.5 nM) and 9i (IC[Formula: see text] 78.3 ± 7.8 nM) exhibited strong inhibitory effects as compared to the standard reference inhibitor. Furthermore, molecular docking and computational analysis provided insight into the binding interactions and supported the observed experimental results by revealing key hydrogen bonding and [Formula: see text]–[Formula: see text] stacking interactions with catalytic residues in the enzyme’s active site. These results suggest that the synthesized Quinoline-based scaffolds are promising lead candidates for further optimization in the development of effective antiviral agents against SARS-CoV-2.