Functionalized Aromatic Sulfones from 1,4‐Benzothiazine‐3‐one‐1,1‐Dioxide: Design, Synthesis, Crystal Structure, and In Silico Evaluation Against SARS‐CoV‐2 Proteins

Abstract This study presents a novel, simple, and efficient method for the synthesis of highly functionalized aromatic sulfones (compounds 4 – 9 ) from a 1,4‐benzothiazine‐1,1‐dioxide derivative bearing an ester group at the N 4 position. The reactivity of the compound was explored through nucleophilic addition and substitution reactions with amines, targeting both the C 3 position and the ester group. Upon heating, the benzothiazine ring underwent opening, accompanied by substitution of the ethoxy group, yielding new sulfones ( 4–9 ) in good yields. The synthesized derivatives were characterized by 1 H and 13 C NMR spectroscopy. Structures of compounds 5 , 7 , and 8 were confirmed by single‐crystal X‐ray diffraction. Additionally, in silico studies were performed to assess the binding interactions between the synthesized compounds and key SARS‐CoV‐2 proteins: 2mm4_Envelope (E), 6y2e_Main Protease (M^pro), 7fcd_Spike (S), and 8cme_Membrane (M), focusing on resistance‐associated mutations (e.g., D614G in Spike or catalytic dyad variants in M^pro). Molecular docking revealed compound L05 exhibited stable interactions with the main protease. Molecular dynamics simulations confirmed these findings, supported by PCA, PDF, and FEL analyses, which demonstrating the conformational stability of the complex and structural adaptations that could potentially affect viral entry, replication, or assembly.