2. Academic Validation
  3. 2,3-Dihydroquinazolin-4(1H)-one derivatives as potent aldose reductase inhibitors: a combined experimental and computational study

2,3-Dihydroquinazolin-4(1H)-one derivatives as potent aldose reductase inhibitors: a combined experimental and computational study

  • Bioorg Chem. 2026 Jun 5:180:110081. doi: 10.1016/j.bioorg.2026.110081.
Feyzi Sinan Tokalı 1,  Yeliz Demir 2,  Nurgül Abul 3,  Halil Şenol 4
Affiliations

Affiliations

  • 1 Department of Material and Material Processing Technologies, Kars Vocational School, Kafkas University, 36100 Kars, Türkiye. Electronic address: [email protected].
  • 2 Department of Pharmacy Services, Nihat Delibalta Göle Vocational High School, Ardahan University, 75700 Ardahan, Türkiye; Department of Chemistry, Faculty of Science, Ataturk University, 25240 Erzurum, Türkiye.
  • 3 Department of Chemistry, Faculty of Science, Ataturk University, 25240 Erzurum, Türkiye.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, Fatih, Istanbul, Türkiye. Electronic address: [email protected].
PMID: 42259147 DOI: 10.1016/j.bioorg.2026.110081
Abstract

A series of sixteen 2,3-dihydroquinazolin-4(1H)-one derivatives was designed and synthesized to evaluate their potential as Aldose Reductase (ALR2) inhibitors for the management of diabetic complications. The synthesized compounds were structurally characterized by FT-IR, NMR, and HRMS analyses, and their inhibitory activities were assessed through in vitro enzyme assays. All compounds exhibited notable ALR2 inhibition, with Ki values ranging from 0.052 to 1.272 μM. Among them, compound 9 demonstrated the highest potency (Ki = 0.052 μM), showing approximately 21-fold stronger activity than the reference inhibitor epalrestat (Ki = 1.124 μM). Structure-activity relationship analysis revealed that para-positioned electron-donating substituents and optimally positioned hydrogen-bond donor groups significantly enhance inhibitory activity, while ortho substitution adversely affects binding due to steric and conformational constraints. The most active inhibiyors exhibited low cytotoxicity against HUVEC cells, with IC50 values ranging from 36.18 to 55.41 μM, indicating that they are not cytotoxic at the concentrations required for effective ALR2 inhibition. Molecular docking and MM-GBSA analyses supported the experimental findings, indicating strong binding affinities for the most active compounds, particularly compounds 9 and 16. Molecular dynamics simulations further confirmed the stability of the 9-ALR2 complex, demonstrating low structural deviations and persistent interactions with key residues, including Trp-20, Val-47, His-110, Trp-219, and Leu-300. In addition, ADME and toxicity predictions suggested that the majority of the compounds possess favorable pharmacokinetic properties and low predicted toxicity profiles. These results highlight the 2,3-dihydroquinazolin-4(1H)-one scaffold as a promising framework for the development of potent ALR2 inhibitors.

Keywords

2,3-dihydroquinazolin-4(1H)-one; ALR2; Aldose reductase; Inhibition; Molecular dynamics.

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