Probing the Inhibitory Potential of Halogenated Symmetrical Formamidine Against MAO‐A and MAO‐B: Structural Elucidation, Molecular Dynamic Simulation and DFT Computational Studies

ABSTRACTA halogenated symmetrical formamidine, N,N′‐bis(3‐chloro‐4‐fluorophenyl)formamidine (FCF) was synthesized by the condensation reaction between triethyl orthoformate and 3‐chloro‐4‐fluoroaniline in 1:2 ratio. The compound FCF was characterized by FT‐IR, mass, NMR (1H and 13C) spectroscopic techniques and the purity was confirmed by elemental analysis. Crystal structural elucidation of FCF showed that it conformed to an E‐anti‐molecular isomer. In the crystal packing system of FCF, there exists N─H⋯N hydrogen bonding intermolecular interactions between the azomethine nitrogen (N‐azomethine) and amine hydrogen (H‐amine) atoms of neighboring molecules resulting in the formation of dimers with an R 8 graph set motif. Hirshfeld surface analysis unraveled that, H⋯H and Cl⋯H intermolecular contacts contributed equally and the most with each of them contributing 14.6% in crystal packing. The geometrical and electronic properties of FCF were investigated using DFT/B3LYP/6‐311++G(d,p) basis sets. Mulliken and MESP analyses identified reactive sites, while FMO studies revealed a HOMO–LUMO gap (4.62 eV) indicative of intermediate reactivity and stability. Molecular docking and molecular dynamics simulations (MDS) were performed to evaluate the inhibitory potential of FCF against monoamine oxidase A (MAO‐A) and monoamine oxidase B (MAO‐B), both are protein targets for managing Parkinson's disease. Docking studies revealed that FCF exhibited superior binding affinity towards both MAO‐A and MAO‐B compared to the reference drugs (harmine and rasagiline) as reflected in its more negative docking scores. MDS analysis was conducted over 100 ns and we found out that FCF demonstrated superior inhibitory potential against MAO‐A and MAO‐B compared to the reference drugs, as indicated by its stronger binding free energies (−38.78 ± 2.62 kcal mol−1 for MAO‐A and −34.15 ± 3.29 kcal mol−1 for MAO‐B) relative to harmine (−32.43 ± 2.26 kcal mol−1) and rasagiline (−32.44 ± 2.65 kcal mol−1). Furthermore, MDS analysis also confirmed the stability of FCF–protein complexes, with lower RMSD values suggesting greater structural stability. In addition, pharmacokinetic analysis revealed that FCF possesses favorable drug‐like properties, including high gastrointestinal absorption, blood–brain barrier permeability, and a nontoxic profile, reinforcing its potential as a promising therapeutic agent for targeting neurodegenerative disorders such as Parkinson's disease.