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<p>Motivated by the need for orally available vanadium-based therapeutics, particularly for Type II diabetes mellitus, a novel series of four mixed-ligand oxovanadium(IV) complexes of the general formula [VO(fmphp)(L)(H₂O)] were synthesized, where fmphpH = 4‑formyl‑3‑methyl‑1‑phenyl‑2‑pyrazolin‑5‑one and L = methyl acetoacetate (<b>1</b>), ethyl acetoacetate (<b>2</b>), benzoyl acetone (<b>3</b>), or dibenzoyl methane (<b>4</b>). Comprehensive structural characterization <i>via</i> elemental analysis, FT‑IR, UV‑Vis, ESI‑MS, EPR, and cyclic voltammetry consistently supported distorted octahedral geometries. Key spectral markers included <i>ν</i>(V = O) stretches between 972 and 991&#xa0;cm⁻¹ and LMCT bands at 405–410&#xa0;nm, while room-temperature magnetic moments (~ 1.9 B.M.) and EPR spectra (gₐ<sub>v</sub> = 2.099, Aₐ<sub>v</sub> = 91.66 G for 1) confirmed the paramagnetic d¹ V(IV) state. DFT calculations at the B3LYP/LANL2DZ level on the representative complex 1 provided detailed electronic insights: a narrowed HOMO–LUMO gap of 2.30 eV (vs. 4.80&#xa0;eV in free ligand), a dipole moment of 6.88 D, and a tenfold increase in first hyperpolarizability (β₀ = 3.16 × 10⁻³⁰ e.s.u.), indicating enhanced polarizability and charge‑transfer character. Crucially, in silico ADMET profiling revealed highly promising pharmacokinetic properties: predicted human intestinal absorption &gt; 74%, topological polar surface area ≤ 96.7 Ų, Log <i>P</i> = 0.00, and zero violations of Lipinski’s rule of five. Additionally, all complexes were predicted to be non‑carcinogenic with favorable acute toxicity profiles (LD₅₀ &gt;1.84&#xa0;mol/kg). These integrated experimental and computational results not only establish the structural and electronic identity of the complexes but also strongly support their drug‑likeness and oral bioavailability, positioning them as lead candidates for further preclinical development in vanadium‑based metallodrug discovery. Meanwhile, the preliminary α-glucosidase inhibition assay suggests IC₅₀ = 16–28 µM provides initial experimental support to suggest the complexes as antidiabetic potential candidates, complementing the in silico ADMET predictions.</p> Graphical abstract <p></p>

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Exploring the α-Glucosidase Inhibition Potential of Mixed-Ligand Oxovanadium(IV) Complexes: A Synthetic, DFT, and In Silico ADMET Study Using Pyrazolone and β-Diketone Scaffolds

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Pradeep Kumar Vishwakarma,
  • Shams H. Abdel-Hafez,
  • Ibrahim S. A. Ahmed,
  • Munirah M. Al-Rooqi,
  • Rabab S. Jassas,
  • Pushpendra Singh Jaget,
  • Ram Charitra Maurya,
  • Ziad Moussa,
  • Jan Mohammad Mir,
  • Saleh A. Ahmed

摘要

Motivated by the need for orally available vanadium-based therapeutics, particularly for Type II diabetes mellitus, a novel series of four mixed-ligand oxovanadium(IV) complexes of the general formula [VO(fmphp)(L)(H₂O)] were synthesized, where fmphpH = 4‑formyl‑3‑methyl‑1‑phenyl‑2‑pyrazolin‑5‑one and L = methyl acetoacetate (1), ethyl acetoacetate (2), benzoyl acetone (3), or dibenzoyl methane (4). Comprehensive structural characterization via elemental analysis, FT‑IR, UV‑Vis, ESI‑MS, EPR, and cyclic voltammetry consistently supported distorted octahedral geometries. Key spectral markers included ν(V = O) stretches between 972 and 991 cm⁻¹ and LMCT bands at 405–410 nm, while room-temperature magnetic moments (~ 1.9 B.M.) and EPR spectra (gₐv = 2.099, Aₐv = 91.66 G for 1) confirmed the paramagnetic d¹ V(IV) state. DFT calculations at the B3LYP/LANL2DZ level on the representative complex 1 provided detailed electronic insights: a narrowed HOMO–LUMO gap of 2.30 eV (vs. 4.80 eV in free ligand), a dipole moment of 6.88 D, and a tenfold increase in first hyperpolarizability (β₀ = 3.16 × 10⁻³⁰ e.s.u.), indicating enhanced polarizability and charge‑transfer character. Crucially, in silico ADMET profiling revealed highly promising pharmacokinetic properties: predicted human intestinal absorption > 74%, topological polar surface area ≤ 96.7 Ų, Log P = 0.00, and zero violations of Lipinski’s rule of five. Additionally, all complexes were predicted to be non‑carcinogenic with favorable acute toxicity profiles (LD₅₀ >1.84 mol/kg). These integrated experimental and computational results not only establish the structural and electronic identity of the complexes but also strongly support their drug‑likeness and oral bioavailability, positioning them as lead candidates for further preclinical development in vanadium‑based metallodrug discovery. Meanwhile, the preliminary α-glucosidase inhibition assay suggests IC₅₀ = 16–28 µM provides initial experimental support to suggest the complexes as antidiabetic potential candidates, complementing the in silico ADMET predictions.

Graphical abstract