Click Chemistry Synthesis, Structural Characterization, and Molecular Modeling of a Novel ML300 Analog and its Bis‐Derivative as SARS‐CoV‐2 M pro Inhibitors

ABSTRACT The main protease (M pro ) of the SARS‐CoV‐2 coronavirus plays a crucial role in viral processing. By blocking its cleavage, one can quickly halt the production of the virus's replication machinery, effectively stopping the viral life cycle. In this study, we propose a strategy for discovering and developing new small‐molecule non‐covalent inhibitors of M pro based on the ML300 scaffold. Using a click chemistry approach, we synthesized a new ML300 analog that features a 4‐phenyl‐1 H ‐1,2,3‐triazol‐1‐yl)‐ N ‐(thiophen‐2‐ylmethyl)acetamide moiety. Furthermore, we discovered that this synthesized analog can form a bis‐derivative, the structure of which was characterized using NMR and X‐ray analysis. Employing a series of computational chemistry tools—including DFT (density functional theory) calculations of structural and electronic properties, as well as molecular docking and molecular dynamics simulations of ligand‐M pro complexes—we demonstrated that the bis‐derivative exhibited superior antiviral potency compared to its monomer and the parent ML300 inhibitor. Our findings describe a promising click chemistry approach for the synthesis of bis‐products of 4‐phenyl‐1H‐1,2,3‐triazol‐1‐yl derivatives as new and effective therapeutics against COVID‐19.