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<p>Pyridazinone-based dissymmetrical scaffolds linked by ethylene (<b>2a</b>) or propylene (<b>2b</b>) spacer were synthesized and characterized to study their crystal structure, intermolecular interactions, and DPP-4 inhibitory activity. Single-crystal X-ray diffraction showed that both compounds form an identical intermolecular amide–amide homo-synthon via N–H⋯O hydrogen bonds, despite <b>2a</b> adopting a folded conformation and <b>2b</b> an open conformation. Hirshfeld surface analysis confirmed that H⋯H, C⋯H C⋯C, O⋯H, and H⋯N contacts dominate the crystal packing (notably strong amide–amide interactions), and interaction energy calculations quantified the amide–amide N–H⋯O bonds as − 76.3&#xa0;kJ·mol⁻¹ (<b>2a</b>) and − 73.1&#xa0;kJ·mol⁻¹ (<b>2b</b>). DFT optimization reproduced the experimental geometries and revealed a slightly larger HOMO–LUMO gap for <b>2b</b> than <b>2a</b> (3.53 vs. 3.49&#xa0;eV), indicating marginally greater electronic stability for <b>2b</b>. Molecular docking against DPP-4 suggested a more favorable predicted binding mode for <b>2a</b> than <b>2b</b> under the applied docking conditions; however, <i>in vitro</i> inhibition data showed that sitagliptin remained substantially more active than both compounds. <i>In vitro</i> DPP-4 assays at 50–100 nM showed measurable preliminary inhibition by both compounds: <b>2a</b> gave ~ 48.6%, 51.3%, and 57.0% inhibition at 50, 75, and 100 nM, respectively, compared with 38.3%, 40.8%, and 57.6% for 2b and 86–92% for sitagliptin. Overall, these pyridazinone dimers are structurally interesting synthon-forming systems and serve as preliminary DPP-4 inhibitory hits worthy of further optimization.</p>

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Development of intermolecular amide-amide hydrogen-bonded synthon: conformational stability and in silico studies

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Akhilesh Kumar,
  • Vipin Kumar,
  • Manisha Nidhar,
  • Suman Gill,
  • Ashish Kumar Tewari

摘要

Pyridazinone-based dissymmetrical scaffolds linked by ethylene (2a) or propylene (2b) spacer were synthesized and characterized to study their crystal structure, intermolecular interactions, and DPP-4 inhibitory activity. Single-crystal X-ray diffraction showed that both compounds form an identical intermolecular amide–amide homo-synthon via N–H⋯O hydrogen bonds, despite 2a adopting a folded conformation and 2b an open conformation. Hirshfeld surface analysis confirmed that H⋯H, C⋯H C⋯C, O⋯H, and H⋯N contacts dominate the crystal packing (notably strong amide–amide interactions), and interaction energy calculations quantified the amide–amide N–H⋯O bonds as − 76.3 kJ·mol⁻¹ (2a) and − 73.1 kJ·mol⁻¹ (2b). DFT optimization reproduced the experimental geometries and revealed a slightly larger HOMO–LUMO gap for 2b than 2a (3.53 vs. 3.49 eV), indicating marginally greater electronic stability for 2b. Molecular docking against DPP-4 suggested a more favorable predicted binding mode for 2a than 2b under the applied docking conditions; however, in vitro inhibition data showed that sitagliptin remained substantially more active than both compounds. In vitro DPP-4 assays at 50–100 nM showed measurable preliminary inhibition by both compounds: 2a gave ~ 48.6%, 51.3%, and 57.0% inhibition at 50, 75, and 100 nM, respectively, compared with 38.3%, 40.8%, and 57.6% for 2b and 86–92% for sitagliptin. Overall, these pyridazinone dimers are structurally interesting synthon-forming systems and serve as preliminary DPP-4 inhibitory hits worthy of further optimization.