Synthesis, crystallographic structure, and antibacterial activity of new pyrene-based hydrazones

Hydrazones are compounds that exhibit a broad range of biological activities, including anticancer, antifungal, antimicrobial, anti-inflammatory, anticonvulsant properties. On the other hand, pyrene is a highly conjugated polycyclic aromatic hydrocarbon that has been used in antimicrobial and bioimaging studies, showing activity against wild-type bacteria and fungal species. In this work, we synthesized new hydrazones derived from 1-pyrenecarboxaldehyde (1) with various para-substituted phenylhydrazines (2a-d) bearing electron-withdrawing groups such as fluorine, chlorine, and bromine, since these halogens are associated with enhanced biological activity and improved permeability. Additionally, an electron-donating group (4-OCH₃) was included due to its prominence in several known derivatives with anticancer activity.

For the synthesis of hydrazones 3a-d, a mixture of 1-pyrenecarboxaldehyde (1) and p-phenylhydrazines (a: 4-Cl, b: 4-Br, c: 4-CF₃, d: 4-OCH₃) was stirred in ethanol at 80 °C, yielding the desired products (3a-d) in 73-90%, which were characterized by IR spectroscopy, ¹H and ¹³C NMR, mass spectrometry, and single-crystal X-ray diffraction of 3d, obtained by slow evaporation from ethanol. Hydrazones 3a-d exhibited bacteriostatic activity against Mycobacterium tuberculosis, and compound 3d was active with a MIC = 40 µg/mL. Moreover, all compounds showed anticancer activity against breast cancer cells (MCF-7) with and IC₅₀ value <6.25 µg/mL, and compound 3d (4-OCH₃) exhibits the highest inhibitory activity against cervical cancer cells (Hep-2) with an IC₅₀ of 67.2 µg/mL. Molecular docking studies were performed using the binding pocket of PDB: 2OZ5. The protein-ligand complex of compound 3d exhibited interactions with catalytic residues Met146, Arg230, and Met226.