Design, Synthesis, In Silico ADMET Profiling, and Molecular Docking of a Novel Bis-dimethylamino Hydrazone as a Potent Dual Inhibitor of Monoamine Oxidases

Abstract

Monoamine oxidases (MAO-A and MAO-B) play a key role in the metabolism of neurotransmitters, and their dysregulation is linked to neurological disorders. Hydrazone scaffolds are known for their versatile biological activities, including MAO inhibition. In this work, a new hydrazone derivative, 4-(Dimethylamino) benzaldehyde (4-dimethylamino) benzylidene hydrazone (DMBH-1), was synthesized through the condensation of hydrazine hydrate with para-dimethylamino benzaldehyde. The reaction produced a yellow crystalline solid with a 65% yield after recrystallization using chloroform. The molecular formula of the compound is C₁₈H₂₂N₄, with a molecular weight of 294.39 g/mol. Structural confirmation was achieved through UV–Visible spectroscopy, FT-IR, 1H and 13C NMR, and mass spectrometry. Molecular target prediction using SwissTargetPredict indicated affinity towards human monoamine oxidases MAO-A and MAO-B. Docking studies were performed using AutoDock against MAO-A PDB structures 2Z5X and 2BXR, and MAO-B structures 1GOS, 2V5Z, and 6FW0. DMBH-1 showed strong binding energies across all targets, with scores of –8.55 kcal/mol (2Z5X) and –8.35 kcal/mol (2BXR) for MAO-A. For MAO-B, the compound showed binding energies of –8.47 (1GOS), –8.74 (2V5Z), and –9.22 kcal/ mol (6FW0). These values were superior to standard MAO-B inhibitors including safinamide (–7.18 to –8.72), rasagiline (–6.88 to –7.11), and selegiline (–6.23 to –6.94). DMBH-1 also showed stronger affinity than MAO-A inhibitors harmine (-7.13 to -7.67), moclobemide (-7.05 to -7.28), and clorgyline (6.35 to 6.60). SwissADME analysis showed favourable properties: molecular weight 294.39 g/mol, TPSA 31.20 Ų, consensus LogP 3.25, high GI absorption, BBB permeability, and no PAINS alerts. The bioavailability score was 0.55 with a synthetic accessibility of 2.38. Overall, DMBH-1 exhibits strong predicted MAO inhibitory activity and promising drug-likeness, indicating good potential as a lead molecule for CNS-related drug discovery.