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

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