Design and synthesis of dual MAO-Aromatase inhibitors containing benzoxazolinone-hydrazone pharmacophore: In silico and in vitro studies

Taşçi, N., Design and synthesis of dual MAO-Aromatase inhibitors containing benzoxazolinone-hydrazone pharmacophore: In silico and in vitro studies, Hacettepe University, Graduate School of Health Sciences PhD Thesis in Pharmaceutical Chemistry, Ankara, 2022. In this study, 43 compounds, 40 of which are original (Compounds 1-43) in N'-substitutedbenzylidene-3-(5-methyl-2-benzoxazolinon-3-yl)propiohydrazide structure were synthesized and their structures were elucidated with spectral data and their purity was confirmed by elemental analysis. The inhibitory effects and selectivity of the compounds on monoamine oxidase isoforms were studied in vitro tests. It was determined that N'-(3-hydroxybenzylidene)-3-(5-methyl-2-benzoxazolinon-3-yl)propiohydrazide (Compound 14) and N'-(4-hydroxybenzylidene)-3-(5-methyl-2-benzoxazolinon-3-yl)propiohydrazide (Compound 15) are the derivatives that inhibit MAO-A and MAO-B at the most effective level, the compounds generally show MAO-B selectivity, the derivative with the highest MAO-A selectivity is N'-(4-nitrobenzylidene)-3-(5-methyl-2-benzoxazolinon-3-yl)propiohydrazide (Compound 18). For the purpose of dual-acting MAO-Aromatase inhibitor compound discovery, compounds showing high MAO-A/B inhibition were selected and their in vitro aromatase inhibitor activities and cytotoxicity in MCF-7 breast cancer cell line were evaluated. It was observed that the compounds generally showed high levels of aromatase inhibitor and cytotoxic activity. The most effective aromatase inhibitor derivative was N'-(3-hydroxybenzylidene)-3-(5-methyl-2-benzoxazolinon-3-yl)propiohydrazide (Compound 14) and the derivative with the highest cytotoxic activity was N'-(3-chlorobenzylidene)-3-(5-methyl-2-benzoxazolinon-3-yl)propiohydrazide (Compound 4). Protein-ligand interactions in the active sites of MAO-A/B enzymes of all compounds and in the aromatase enzyme active site of selected compounds were investigated.