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