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<p>Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia. Targeting α-amylase, a key enzyme involved in carbohydrate digestion, offers an effective strategy to manage postprandial glucose levels. In this study, a series of 31 novel thiazolidinedione-oxadiazole derivatives (<b>SA1–SA31</b>) were designed using pharmacophore-based strategies to incorporate diverse electron-withdrawing (EWGs) and electron-donating groups (EDGs). Molecular docking against α-amylase (PDB ID: 4W93) revealed superior binding affinities for compounds <b>SA25</b> and <b>SA31</b> (-10.3 and − 10.6&#xa0;kcal/mol, respectively) compared to the standard drug Acarbose (-6.7&#xa0;kcal/mol). Structure–activity relationship (SAR) analysis highlighted the significance of <i>para</i>-positioned EWGs in enhancing binding potential. ADME analysis of the top 15 compounds demonstrated favorable pharmacokinetic profiles with high gastrointestinal absorption and no Lipinski rule violations. Eight compounds were synthesized and characterized; their α-amylase inhibitory activities were evaluated. <b>SA16</b> and <b>SA19</b> showed potent inhibition with IC<sub>50</sub> values of 9.15&#xa0;µg/mL and 22.65&#xa0;µg/mL, respectively. A Ramachandran plot analysis confirmed the structural validity of the target protein with 92.1% residues in favored regions. These findings underscore the potential of thiazolidinedione-oxadiazole hybrids as promising antidiabetic candidates and warrant further in vivo validation.</p>

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Design and evaluation of novel thiazolidinedione-oxadiazole derivatives as potent α-amylase inhibitors for antidiabetic therapy

  • 期刊论文

  • 发表日期：

    2025年6月27日

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  • Pinky Arora,
  • Aditi Rana,
  • Azmat Ali Khan,
  • Amer M. Alanazi,
  • Pankaj Wadhwa,
  • Sonia Singla,
  • Shubham Kumar,
  • Rubal kalra

摘要

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia. Targeting α-amylase, a key enzyme involved in carbohydrate digestion, offers an effective strategy to manage postprandial glucose levels. In this study, a series of 31 novel thiazolidinedione-oxadiazole derivatives (SA1–SA31) were designed using pharmacophore-based strategies to incorporate diverse electron-withdrawing (EWGs) and electron-donating groups (EDGs). Molecular docking against α-amylase (PDB ID: 4W93) revealed superior binding affinities for compounds SA25 and SA31 (-10.3 and − 10.6 kcal/mol, respectively) compared to the standard drug Acarbose (-6.7 kcal/mol). Structure–activity relationship (SAR) analysis highlighted the significance of para-positioned EWGs in enhancing binding potential. ADME analysis of the top 15 compounds demonstrated favorable pharmacokinetic profiles with high gastrointestinal absorption and no Lipinski rule violations. Eight compounds were synthesized and characterized; their α-amylase inhibitory activities were evaluated. SA16 and SA19 showed potent inhibition with IC50 values of 9.15 µg/mL and 22.65 µg/mL, respectively. A Ramachandran plot analysis confirmed the structural validity of the target protein with 92.1% residues in favored regions. These findings underscore the potential of thiazolidinedione-oxadiazole hybrids as promising antidiabetic candidates and warrant further in vivo validation.