A new fluorinated hydrazone derivative as a multitarget therapeutic agent: Synthesis, crystal structure, spectroscopic characterization, Hirshfeld surface analysis, DFT/TD-DFT studies, NLO properties, in silico molecular docking, ADMET profiling, and biomimetic oxidation activity

Abstract

A new hydrazone molecule HL: (E)-2-fluoro-N'-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene)benzohydrazide, was synthesized by condensation of 2-fluorobenzohydrazide with dehydroacetic acid. The structure of HL was confirmed using spectroscopic analysis, including NMR (¹H, ¹³C), UV-visible and infrared, and single crystal X-ray diffraction. This compound adopted a zwitterionic form HL’ stabilized by intramolecular hydrogen bonding interactions between [N⁺—H…^-O] groups and crystallized in the monoclinic system with space group P2₁/c. Indeed, Hirshfeld surface analysis was performed to visualize and quantify the intermolecular interactions within the crystalline structure, revealing the presence of intermolecular contacts involving H···Ο and H···F hydrogen bonds and non-conventional C–H···H, C–H···π, and π···lp interactions, as well as π–π stacking. DFT calculations were carried out using the ωB97X-D functional with the 6-31+G(d) basis set. Based on DFT conceptual principles, key global molecular reactivity descriptors were obtained, including chemical hardness, electronic chemical potential, electronegativity, and electrophilicity index. Furthermore, the nonlinear optical properties of the compound HL and its tautomer HL ↔ HL’’ were explored, revealing promising potential for applications in second- and third-order NLO materials. Molecular docking studies were also conducted to evaluate the in silico biological activity of HL against cholinesterase enzymes, specifically acetylcholinesterase and butyrylcholinesterase. Furthermore, the physicochemical and pharmacokinetic properties of the molecule were assessed through ADMET analysis, confirming its favorable drug-likeness characteristics. In this study, we aim to evaluate the catalytic activity of in-situ complexes formed using HL as a catalyst with Cu^II salts, which are commonly used in the oxidation of catechol to o-quinone.