Development of Coumarin-Sulfonamide Derivatives as Versatile Polyphenol Oxidase Inhibitors With Favorable Physicochemical and Pharmacokinetic Profiles
Biotechnology and Applied Biochemistry, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/bab.70198
- Dergi Adı: Biotechnology and Applied Biochemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, BIOSIS, Chemical Abstracts Core, Compendex, EMBASE, Environment Index, INSPEC, MEDLINE, Academic Search Ultimate (EBSCO), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Biomedical Reference Collection: Corporate Edition (EBSCO), Engineering Source (EBSCO), Health Research Premium Collection (ProQuest)
- Anahtar Kelimeler: DFT, molecular docking, molecular electronic potential, polyphenol oxidase (PPO), sulfonamide
- Kocaeli Üniversitesi Adresli: Evet
Özet
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 1H-NMR. Enzyme kinetics against Agaricus bisporus tyrosinase revealed competitive inhibition across the series, with Ki 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 λ2ρ ≈ −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 (IC50 = 103 ± 5.64 µM; Ki = 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; IC50 = 99.7 ± 0.91 µM; Ki = 57 uM) achieved comparable inhibition through a distinctive π–sulfur interaction with His85 and copper coordination. DS-6 (N-ethyl-N-phenyl; IC50 = 90.3 ± 4.86 µM; Ki = 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.