Development of Coumarin‐Sulfonamide Derivatives as Versatile Polyphenol Oxidase Inhibitors With Favorable Physicochemical and Pharmacokinetic Profiles

ABSTRACT Enzymatic browning mediated by polyphenol oxidase (PPO) remains a persistent challenge in food preservation. We report the rational design, synthesis, and evaluation of nine coumarin‐sulfonamide hybrid inhibitors (DS1‐9) featuring 6,7‐dihydroxy‐2‐oxo‐2H‐chromen‐4‐yl cores linked to N‐substituted benzenesulfonamide scaffolds, confirmed by FT‐IR and 1 H‐NMR. Enzyme kinetics against Agaricus bisporus tyrosinase revealed competitive inhibition across the series, with K i values spanning 46–775 uM. DFT calculations (B3LYP/def2‐TZVP) characterized the electronic landscape, HOMO‐LUMO energies (−5.716 to −6.455 eV; −1.716 to −2.278 eV), electrophilicity indices (3.5–4.2 eV), and dipole moments (4.98–11.24 Debye), while C‐PCM solvation modeling, MEP mapping, and RDG analysis established that intramolecular hydrogen bonding (sign λ 2 ρ ≈ −0.025 to −0.035 a.u.) preorganizes binding‐competent conformations. Molecular docking against PPO3 (PDB: 2Y9X) yielded binding affinities of −7.66 to −8.99 kcal/mol, substantially exceeding tropolone (−4.65 kcal/mol). DS‐7 ( N ‐3,4‐dimethylisoxazol‐5‐yl) emerged as the lead compound (IC 50 = 103 ± 5.64 µM; K i = 46 uM), its potency driven by hydrogen bonding with Glu322, His85, and Asn260 alongside π–sigma/π–anion contacts. DS‐1 ( N ‐thiazol‐2‐yl; IC 50 = 99.7 ± 0.91 µM; K i = 57 uM) achieved comparable inhibition through a distinctive π–sulfur interaction with His85 and copper coordination. DS‐6 ( N ‐ethyl‐ N ‐phenyl; IC 50 = 90.3 ± 4.86 µM; K i = 129 uM) outperformed docking predictions via apparent induced‐fit binding involving dual copper π–alkyl coordination. SAR analysis identified the 6,7‐dihydroxycoumarin core, Val283 π–sigma anchoring, and lipophilic N‐substitution as non‐negotiable pharmacophoric elements, positioning DS‐7, DS‐1, and DS‐6 for food preservation and biocatalytic applications.