Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, , , and , and were developed and examined for their ability to inhibit MAO. Among them, compound showed a strong MAO-B inhibitory effect with an IC () value of 1.672 μM, followed by (IC = 16.934 μM). Additionally, showed the highest selectivity index (SI) value of >23.92. The effectiveness of was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the series, (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH, -CH, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, was a reversible inhibitor with a K value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.