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. 2023 Aug 21;28(16):6167.
doi: 10.3390/molecules28166167.

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

Amritha Manoharan  1 , Jong Min Oh  2 , Feba Benny  1 , Sunil Kumar  1 , Mohamed A Abdelgawad  3   4 , Mohammed M Ghoneim  5   6 , Mohamed E Shaker  7   8 , Mohamed El-Sherbiny  9   10 , Hailah M Almohaimeed  11 , Prashant Gahtori  12 , Hoon Kim  2 , Bijo Mathew  1
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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

Amritha Manoharan et al. Molecules. .

Abstract

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, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 μM, followed by IHC2 (IC50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 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 IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Keywords: indole-based phenylallylidene derivatives; kinetics; molecular docking; monoamine oxidase inhibitors; neurological diseases; neuroprotection; reversibility.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Synthesis of indole-based phenylallylidene derivatives. 1, substituted isatin; 2, hydrazine; 3, isatin-hydrazide; 4, substituted cinnamaldehyde.
Figure 2
Figure 2
Structures of lead compounds as MAO-B inhibitor, compared to IHC3. References cited were represented. Compound 14 [14], BCH2 [42], Compound 1f [43], Compound 3 [29] and A3 [44].
Figure 3
Figure 3
Structure-activity relationship of indole-based phenylallylidene derivatives.
Figure 4
Figure 4
Recovery of MAO-B inhibition by IHC3 using dialysis experiments. The concentrations of safinamide (reversible MAO-B inhibitor), pargyline (an irreversible MAO-B inhibitor), and IHC3 used were ~2.0 times their IC50 values (0.04, 0.28, and 3.20 μM, respectively). After preincubation for 30 min, the mixtures were dialyzed for 6 h, with two buffer changes.
Figure 5
Figure 5
Lineweaver-Burk plots for the MAO-B inhibition activity of IHC3 (A) and its secondary plot (B) of the slopes vs. inhibitor concentrations. The experiments were analyzed at five concentrations of benzylamine as a substrate and three inhibitor concentrations.
Figure 6
Figure 6
(A) Graphical representation depicting the neuroprotective effect of IHC3 on rotenone-induced SHSY5Y cells by MTT assay. Y-axis, percentage viability; X-axis, concentration of IHC3. All experiments were done in triplicates and results represented as mean ± SE. One-way ANOVA and Dunnets test were performed to analyze data. *** p < 0.001 compared to control groups. (B) Rotenone-induced morphological aberration in SH-SY5Y cells.
Figure 7
Figure 7
(A) Binding interactions of the compound IHC3 to the active site of the hMAO-B enzyme (PDB ID: 2V5Z). (B) 3D binding poses of FAD (yellow), safinamide (green), and IHC3 (red).
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