Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors

Abstract

The aim of this study was to design novel multifunctional neuroprotective agents that would slow down or halt neurodegeneration through inhibition of MAO-A, MAO-B and caspase-3. We focused on pharmacophoric groups of known MAO-inhibitors including selegiline (propargylamine moiety) and safinamide (fluorobenzyl moiety), and isatin sulfonamide caspase-3 inhibitors. The synthesised compounds consisted of the isatin nucleus conjugated to a fluorophenylsulfonyl moiety at position 5 and on selected compounds a propargylamine moiety was introduced at the N-position of isatin. All the compounds showed promising MAO-A inhibitory activity (IC₅₀: 4–22 μM). The compounds without the propargylamine moiety showed better MAO-B inhibition (IC₅₀: 5–8 μM) and caspase-3 inhibition (IC₅₀: 25–29 μM). The fluorophenylsulfonyl moiety in the synthesized compounds was significant for their multifunctional activity. In general the active compounds showed similar or improved inhibitory activities when compared to the reference compounds isatin (MAO-A and -B) and Z-VAD-FMK (caspase-3). Possible binding orientations of selected isatin analogues within the active site cavities of MAO-A, -B and caspase-3 are proposed and in silico ADMET studies were also done. N-[(3-Fluorophenyl)methyl]-N-methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonamide (4) and N-[(4-fluorophenyl)methyl]-N-methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonamide (5) showed the best multifunctional neuroprotective potential and can be considered as new lead compounds for the development of alternative treatment options for neurodegenerative disorders such as AD, PD and HD.