Structural Investigation of Invertomeric 3‐(phenylsulfinyl)‐2 <i>H</i> ‐chromen‐2‐one for Interaction With Human Serum Albumin

ABSTRACT Novel coumarin derivatives exhibit strong antibacterial activity against MRSA, offering promise in combating antibiotic resistance. They also function as selective PET tracers, interacting with monoamine oxidase B (MAO‐B) to advance neurological research. Here, we examine 3‐(phenylsulfinyl)‐2 H ‐chromen‐2‐one, a compound featuring an asymmetric sulfur atom. This structural element restricts conjugation between coumarin and phenyl rings, producing a flexible molecule with rotatable parts. Such flexibility increases electrophilicity in solution relative to the crystalline form, enhancing protein interactions. Binding studies with human serum albumin (HSA), a key drug‐transport protein, revealed a strong affinity 1.80 ± 0.03 × 10 4 M −1 , supported by warfarin, ibuprofen, and ANS assays. Computational solid‐state DFT, analyses from quantum chemistry, electron localization descriptors (such as ELF, LOL, EDDB), and docking simulations with HSA showcase a wide range of methodologies and rigorous approaches. The compound's invertomeric chiral sulfur atom enables interconvertible R‐ and S‐enantiomers, which show distinct free energy changes upon binding. Results indicate the R‐enantiomer binds more favorably to HSA, underscoring the importance of chirality in protein–ligand interactions.