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<p>Alkaline phosphatase (ALP) and <i>α-</i>amylase are clinically relevant biomarkers for metabolic disorders, including diabetes and hepatobiliary dysfunction. This study reports the synthesis of sulfanilamide-linked triazolo–oxadiazole derivatives (<b>7a–j</b>) using click chemistry and their evaluation as dual enzyme inhibitors. Spectroscopic analysis were employed to validate structure of the synthesized compounds. Biological evaluation revealed that all compounds exhibited moderate inhibition against both enzymes. Compound <b>7e</b> demonstrated the lowest IC<sub>50</sub> against <i>α</i>-amylase at 48.11 µM, while compound <b>7i</b> showed the lowest IC<sub>50</sub> against ALP at 41.99 µM. In silico methods, were employed to guide compounds prioritization and interpret experimental outcomes. Docking scores ranged from − 8.4 to − 9.4&#xa0;kcal/mol for <i>α-</i>amylase and − 8.3 to − 9.0&#xa0;kcal/mol for ALP, consistent with experimental trends. DFT analysis revealed that smaller HOMO-LUMO gaps (3.92–4.55&#xa0;eV) were correlated with enhanced chemical reactivity. ADMET profiling revealed that high TPSA values (163.47–172.70 Ų), predict low GI absorption, an inherent trade-off between polarity required for binding and membrane permeability, hence best suited for parenteral delivery or as lead scaffolds for optimization and limit oral bioavailability. No PAINS or Brenk alerts were detected, all compounds satisfied Lipinski’s rule of five, and they lacked oral drug-likeness due to poor permeability. They are therefore best suited for parenteral delivery or as lead scaffolds for further optimization.</p> Graphical abstract <p></p>

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Integrated synthesis and computational assessment of sulfanilamide–triazolo–oxadiazole triads as effective ALP and amylase inhibitors

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Bisma Iqbal,
  • Aamer Saeed,
  • Mian Bilal Haider,
  • Hammad Ismail,
  • Guoqiang Yang,
  • Abdullah Tariq,
  • Basant Farag,
  • Sobhi M. Gomha,
  • Hesham R. El-Seedi

摘要

Alkaline phosphatase (ALP) and α-amylase are clinically relevant biomarkers for metabolic disorders, including diabetes and hepatobiliary dysfunction. This study reports the synthesis of sulfanilamide-linked triazolo–oxadiazole derivatives (7a–j) using click chemistry and their evaluation as dual enzyme inhibitors. Spectroscopic analysis were employed to validate structure of the synthesized compounds. Biological evaluation revealed that all compounds exhibited moderate inhibition against both enzymes. Compound 7e demonstrated the lowest IC50 against α-amylase at 48.11 µM, while compound 7i showed the lowest IC50 against ALP at 41.99 µM. In silico methods, were employed to guide compounds prioritization and interpret experimental outcomes. Docking scores ranged from − 8.4 to − 9.4 kcal/mol for α-amylase and − 8.3 to − 9.0 kcal/mol for ALP, consistent with experimental trends. DFT analysis revealed that smaller HOMO-LUMO gaps (3.92–4.55 eV) were correlated with enhanced chemical reactivity. ADMET profiling revealed that high TPSA values (163.47–172.70 Ų), predict low GI absorption, an inherent trade-off between polarity required for binding and membrane permeability, hence best suited for parenteral delivery or as lead scaffolds for optimization and limit oral bioavailability. No PAINS or Brenk alerts were detected, all compounds satisfied Lipinski’s rule of five, and they lacked oral drug-likeness due to poor permeability. They are therefore best suited for parenteral delivery or as lead scaffolds for further optimization.

Graphical abstract