Pyridazine- and triazine–acetophenone derivatives: synthesis, crystal structure, Hirshfeld surface, DFT analysis, and multitarget docking against DPP-4/CYP7A1/GSK-3β

A series of pyridazine- and triazine–acetophenone derivatives (1a–1d, 2a–2d) were designed and synthesized via nucleophilic substitution of substituted phenacyl bromides with the corresponding pyridazine or triazine precursors. The structures of all compounds were confirmed by ¹H NMR, ¹³C NMR, HRMS, and FT-IR spectroscopy. Single-crystal X-ray diffraction analysis of representative compound 1a revealed an almost perpendicular orientation between the pyridazine and acetophenone fragments (θ ≈ 82.8°), with crystal packing stabilized by weak C–H···O/N and C–H···π interactions. Hirshfeld surface analysis and two-dimensional fingerprint plots quantified the dominant intermolecular contacts, supporting the observed packing features. Density functional theory calculations, including conformational analysis and frontier molecular orbital studies, further complemented the experimental findings by rationalizing the preferred geometry and electronic properties of the compounds. Molecular docking studies against DPP-4, CYP7A1, and GSK-3β were performed to explore potential binding modes, identifying 2a, 2b, and 1b as the most promising DPP-4 binders, 1b, 1d, and 1a for CYP7A1, and 2d, 2c, and 1d for GSK-3β. In vitro DPP-4 inhibition assays further supported these results, with compounds 2b and 1b emerging as the most active derivatives, exhibiting activity comparable to teneligliptin. Overall, the combined crystallographic, computational, and preliminary biological investigations establish the structural and functional relevance of this scaffold and highlight its potential for further optimization as a multitarget therapeutic candidate.