Investigating the Inhibitory Potential of Halogenated Quinoline Derivatives against MAO‑A and MAO-B: Synthesis, Crystal Structure, Density Functional Theory, and Molecular Dynamics Simulations.

Two halogenated quinoline derivatives, namely, -(4-fluorophenyl)-1-(quinoline-2-yl)-methanimine () and -(3-chloro-4-fluorophenyl)-1-(quinoline-2-yl)-methanimine () were synthesized and elucidated by spectroscopic techniques. The molecular structures of and revealed that the azomethine functional group in both compounds is coplanar to the quinoline ring as well as the phenyl ring, as is evident by N2-C8-C7-N1 and C7-N1-C4-C3 torsion angles. In the crystal packing of both compounds, there exists intermolecular CH···N hydrogen bonding. In silico approaches were explored to probe the inhibitory potential of the two compounds against MAO-A and MAO-B, proteins that have been implicated in Parkinson's and neurodegenerative diseases. Docking studies revealed that and exhibit superior binding affinities compared to reference drugs, with demonstrating a binding score of -7.24 kcal/mol for MAO-A and -8.37 kcal/mol for MAO-B, outperforming harmine (-6.57 kcal/mol) and rasagiline (-6.47 kcal/mol). Thermodynamic analysis further confirmed the stability of and interactions, with Δ values of -38.24 and -35.80 kcal/mol for MAO-A, respectively, surpassing that of harmine (-27.82 kcal/mol). Similarly, for MAO-B, and achieved Δ bind values of -35.02 and -33.49 kcal/mol, respectively, exceeding rasagiline (-32.95 kcal/mol). Post-MD simulations analysis revealed that the complexes of / with MAO-A and MAO-B displayed stronger structural stability than reference drugs, as depicted by their lower RMSF, RMSD, and RoG values. For MAO-A, harmine (reference drug) had an RMSD of 3.508 ± 1.328 Å, RoG of 24.916 ± 0.364 Å, and RMSF of 5.990 ± 2.984 Å, whereas , which outshined both reference drug and , had an RMSD of 2.683 ± 0.625 Å, RoG of 24.890 ± 0.198 Å, and RMSF of 6.307 ± 2.580 Å. Quantum chemical calculations and charge distribution parameters were done in gaseous and aqueous phases using different basis sets. Compound was observed to be more chemically reactive and less stable due to its lower energy band gap (Δ) relative to that of . The influence of solvation was quantified, showing that aqueous environment enhances molecular stability and reduces reactivity.