Design, synthesis, and evaluation of 1, 3-dioxo-N-phenylisoindoline-5-carboxamide derivatives as potent reversible inhibitors of human monoamine oxidase B with neuroprotective properties.

A series of 1, 3-dioxo-N-phenylisoindoline-5-carboxamide derivatives were designed, synthesised and evaluated as potent human monoamine oxidase B (hMAO-B) inhibitors with neuroprotective properties. The structure-activity relationship (SAR) was summarised. The most potent compound identified in the study, compound 16, exhibited significant hMAO-B inhibition (IC50 = 0.011 μM) and remarkable selectivity (selectivity index > 3636) over hMAO-A. Kinetic analysis confirmed that compound 16 acted as a mixed-type, reversible hMAO-B inhibitor. Molecular docking studies provided insights into the interactions between the inhibitor and the enzyme. In cellular assays, compound 16 significantly reduced the production of nitric oxide (NO) and tumour necrosis factor-alpha (TNF-α) in lipopolysaccharide (LPS)-stimulated BV-2 cells. Additionally, compound 16 also exhibited notable antioxidant activity. These findings suggested that compound 16 could be developed as a promising lead for further investigation.