Microwave-Assisted Synthesis of Morpholine-Based Chalcones as Reversible MAO-A Inhibitors in the Management of Mental Depression

<b>Background:</b> Depression is one of the most serious and common health problems among the youth population and is responsible for the initiation of many diseases. As per the World Health Organization, 3.8% of the population suffers from mental depression, globally. The monoamine oxidase-A (MAO-A) enzyme is responsible for the degradation of neurotransmitters leading to lower levels of neurotransmitters. <b>Methods</b>: Chalcones (C1-C15) were synthesized by reacting substituted acetophenone with various benzaldehydes in a basic ethanolic solvent at 80 °C under microwave irradiation conditions. To compare the reaction time and product yield, a conventional method of synthesis of chalcones was also performed. The synthesized chalcones (C1-C15) were spectroscopically characterized and screened initially for inhibitory activities against MAO-A and MAO-B. The best active compounds were undertaken for IC₅₀ determination against MAO-A enzyme followed by the reversibility of inhibition analysis and the antioxidant assay. Moreover, in silico molecular docking and ADME pharmacokinetic investigations were accomplished. <b>Results</b>: Most of the compounds inhibited MAO-A, specifically, compounds C14 and C6 exhibited the highest inhibition at IC₅₀ values of 7.91 ± 0.08 μM and 8.45 ± 0.19 μM, respectively. Both these compounds exhibited a reversible MAO-A inhibition displaying up to 60% recovery of enzymatic activity when diluted with substrate (Tyramine). The results of the in silico study indicated docking scores of -9.56 Kcal/mol (C14) and -9.45 Kcal/mol (C6) and exhibited a π-π stacking interaction with the crucial amino acid Trp-397. The compounds were determined to cross the blood-brain barrier (BBB) and displayed favorable gastrointestinal (GI) absorption. Further, the antioxidant assay results demonstrated that the synthesized compounds possess modest free radical scavenging potential. <b>Conclusions</b>: This study displayed the MAO-A inhibitory potential of morpholine-substituted chalcones as a promising pharmacophore for the development of novel antidepressant lead compounds.