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<p>Two new 2(E)-pyranylidene-1,5-benzodiazepine derivatives, namely: 3,4-Dihydro-2-(2,4-dioxo-6-methylpyran-3-ylidene)-4-(3-pyridine-phenyl)-1,5-benzodiazepine <b>3</b> and 2(E)-3,4-Dihydro-2-(2,4-dioxo-6-methylpyran-3-ylidene)-4-(3,4,5-méthoxy-phenyl)-5-N-acetyl-1,5-benzodiazepine<b> 6</b> was synthesized and characterized by NMR spectroscopy and were also analyzed by single-crystal X-ray diffraction. Their molecular packing and supramolecular features were investigated through Hirshfeld surface analysis and interaction energy calculations, which revealed dominant H···H contacts along with secondary C–H···O and π···π interactions. Molecular docking studies performed with the human α1β3γ2 GABAA receptor (PDB: 6HUO) showed favorable binding affinities, suggesting efficient interaction with the benzodiazepine binding site. Furthermore, drug-likeness and ADMET properties assessments indicate that both compounds comply with Lipinski and Veber rules, exhibit good predicted oral absorption, and are in the drug-like space. Compound<b> 3</b> emerges as a promising candidate, with improved permeability and a more favorable toxicity profile. In contrast, compound <b>6</b> exhibits greater intrinsic solubility and prolonged systemic exposure, albeit with a potential hepatotoxicity signal. These results highlight the potential of 2(E)-pyranylidene-1,5-benzodiazepine skeletons as promising candidates for further biological evaluation and the design of novel GABAA receptor modulators.</p><p></p>

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Crystal Structures, Hirshfeld Surface Analysis, Interaction Energies and Molecular Docking Studies of New 2(E)-Pyranylidene-1,5-Benzodiazepine Derivatives

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Imane Faraj,
  • Ayoub El-Mrabet,
  • Kostiantyn V. Domasevitch,
  • Blacque Olivier,
  • Joel T. Mague,
  • Lhoussaine El Ghayati,
  • El Mokhtar Essassi,
  • Nada Kheira Sebbar

摘要

Two new 2(E)-pyranylidene-1,5-benzodiazepine derivatives, namely: 3,4-Dihydro-2-(2,4-dioxo-6-methylpyran-3-ylidene)-4-(3-pyridine-phenyl)-1,5-benzodiazepine 3 and 2(E)-3,4-Dihydro-2-(2,4-dioxo-6-methylpyran-3-ylidene)-4-(3,4,5-méthoxy-phenyl)-5-N-acetyl-1,5-benzodiazepine 6 was synthesized and characterized by NMR spectroscopy and were also analyzed by single-crystal X-ray diffraction. Their molecular packing and supramolecular features were investigated through Hirshfeld surface analysis and interaction energy calculations, which revealed dominant H···H contacts along with secondary C–H···O and π···π interactions. Molecular docking studies performed with the human α1β3γ2 GABAA receptor (PDB: 6HUO) showed favorable binding affinities, suggesting efficient interaction with the benzodiazepine binding site. Furthermore, drug-likeness and ADMET properties assessments indicate that both compounds comply with Lipinski and Veber rules, exhibit good predicted oral absorption, and are in the drug-like space. Compound 3 emerges as a promising candidate, with improved permeability and a more favorable toxicity profile. In contrast, compound 6 exhibits greater intrinsic solubility and prolonged systemic exposure, albeit with a potential hepatotoxicity signal. These results highlight the potential of 2(E)-pyranylidene-1,5-benzodiazepine skeletons as promising candidates for further biological evaluation and the design of novel GABAA receptor modulators.