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<p>A novel series of thiosemicarbazone derivatives <b>6(a–i)</b>, synthesized from 4-formyl-2-nitrophenyl quinoline-8-sulfonate, was evaluated for its antidiabetic potential. Among them, compound <b>6i</b> (IC₅₀ = 54.51 ± 0.84 µM) displayed the most potent α-glucosidase inhibition, whereas <b>6e</b> (IC₅₀ = 9.66 ± 0.14 µM) exhibited superior α-amylase inhibition, indicating their dual therapeutic potential against key carbohydrate-hydrolyzing enzymes implicated in postprandial hyperglycemia. These derivatives showed structural diversity with potent and selective inhibition profiles. Structure-activity relationship analysis revealed that electron-withdrawing substituents enhanced enzyme affinity and biological activity. However, molecular docking studies demonstrated strong binding affinities for compounds <b>6f</b> and <b>6b</b> with docking scores of − 9.1 to − 10.4&#xa0;kcal/mol against target proteins, via hydrogen bonding and π–π interactions with catalytic residues. Furthermore, in-silico ADMET evaluation predicted good oral bioavailability, low toxicity, and favorable pharmacokinetic properties. The Density Functional Theory (DFT) calculations supported experimental results, where studied compounds showed lower HOMO-LUMO energy gaps (2.41–3.42&#xa0;eV), suggesting their significant chemical reactivity and molecular stability of these compounds. Overall, in-vitro and in-silico studies revealed that compounds <b>6b</b>, <b>6f</b>, <b>6e</b>, and <b>6i</b> emerged as promising lead molecules for developing dual-action therapeutic agents targeting hyperglycemia and oxidative damage in diabetes management.</p>

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Design, synthesis, pharmacological evaluation and computational modeling of 4-formyl-2-nitrophenyl quinoline-8-sulfonate derived thiosemicarbazones as antidiabetic agents

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • Muhammad Tayyab,
  • Khalid Mahmood,
  • Khawar Abbas,
  • Farhan Siddique,
  • Nastaran Sadeghian,
  • Halil Şenol,
  • Maryam Bashir,
  • Parham Taslimi,
  • Abdullah K. Alanazi,
  • Mostafa A. Ismail,
  • Xianliang Zhao,
  • Zahid Shafiq

摘要

A novel series of thiosemicarbazone derivatives 6(a–i), synthesized from 4-formyl-2-nitrophenyl quinoline-8-sulfonate, was evaluated for its antidiabetic potential. Among them, compound 6i (IC₅₀ = 54.51 ± 0.84 µM) displayed the most potent α-glucosidase inhibition, whereas 6e (IC₅₀ = 9.66 ± 0.14 µM) exhibited superior α-amylase inhibition, indicating their dual therapeutic potential against key carbohydrate-hydrolyzing enzymes implicated in postprandial hyperglycemia. These derivatives showed structural diversity with potent and selective inhibition profiles. Structure-activity relationship analysis revealed that electron-withdrawing substituents enhanced enzyme affinity and biological activity. However, molecular docking studies demonstrated strong binding affinities for compounds 6f and 6b with docking scores of − 9.1 to − 10.4 kcal/mol against target proteins, via hydrogen bonding and π–π interactions with catalytic residues. Furthermore, in-silico ADMET evaluation predicted good oral bioavailability, low toxicity, and favorable pharmacokinetic properties. The Density Functional Theory (DFT) calculations supported experimental results, where studied compounds showed lower HOMO-LUMO energy gaps (2.41–3.42 eV), suggesting their significant chemical reactivity and molecular stability of these compounds. Overall, in-vitro and in-silico studies revealed that compounds 6b, 6f, 6e, and 6i emerged as promising lead molecules for developing dual-action therapeutic agents targeting hyperglycemia and oxidative damage in diabetes management.