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, <i>N</i>-(4-fluorophenyl)-1-(quinoline-2-yl)-methanimine (<b>Q4F</b>) and <i>N</i>-(3-chloro-4-fluorophenyl)-1-(quinoline-2-yl)-methanimine (<b>Q3Cl4F</b>) were synthesized and elucidated by spectroscopic techniques. The molecular structures of <b>Q4F</b> and <b>Q3Cl4F</b> 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 <b>Q3Cl4F</b> and <b>Q4F</b> exhibit superior binding affinities compared to reference drugs, with <b>Q3Cl4F</b> 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 <b>Q3Cl4F</b> and <b>Q4F</b> interactions, with Δ<i>G</i> _bind 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, <b>Q3Cl4F</b> and <b>Q4F</b> achieved Δ<i>G</i> 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 <b>Q4F</b>/<b>Q3Cl4F</b> 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 <b>Q3Cl4F</b>, which outshined both reference drug and <b>Q4F</b>, 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 <b>Q4F</b> was observed to be more chemically reactive and less stable due to its lower energy band gap (Δ<i>E</i>) relative to that of <b>Q3Cl4F</b>. The influence of solvation was quantified, showing that aqueous environment enhances molecular stability and reduces reactivity.