The evaluation of isatin analogues as inhibitors of monoamine oxidase

Prinsloo, Izak F.; Petzer, Jacobus P.; Cloete, Theunis T.; Petzer, Anél

doi:10.1111/cbdd.14304

Cited by 2 publications

(3 citation statements)

References 34 publications

(51 reference statements)

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“…Among them, compound IHC3 showed less than 50% residual activity against MAO-B at a concentration of 10 µM, with an IC 50 value of 1.672 μM, followed by IHC2 (IC 50 = 16.934 μM) ( Table 1 ). The IC 50 value of IHC3 was lower than the indol and 1-(3-(benzyloxy)benzyl)piperazine 14 (IC 50 = 8.65 μM)[ 41 ], but higher than the benzimidazole chalcone derivative BCH2 (IC 50 = 0.80 μM) [ 42 ], isatin analog 1f (IC 50 = 0.125 μM) [ 43 ], piperonylic acid-derived hydrazone bearing isatin 3 (IC 50 = 0.034 μM) [ 29 ] and isatin derivative A3 (IC 50 = 0.003 μM) [ 44 ] ( Figure 2 ). In addition, IHC3 had the highest selectivity index (SI) value (> 23.92), indicating that it is a selective MAO-B inhibitor ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

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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

Manoharan,

Oh,

Benny

et al. 2023

Molecules

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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.

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Section: Resultsmentioning

confidence: 99%

“…References cited were represented. Compound 14 [ 14 ], BCH2 [ 42 ], Compound 1f [ 43 ], Compound 3 [ 29 ] and A3 [ 44 ].…”

Section: Figurementioning

confidence: 99%

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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

Manoharan,

Oh,

Benny

et al. 2023

Molecules

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Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

Maliyakkal,

Oh,

Kumar

et al. 2024

Appl Biol Chem

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Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 µM), followed by IB3 (IC50 = 0.019 µM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 µM), followed by IB4 (IC50 = 1.87 µM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B. Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.

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The evaluation of isatin analogues as inhibitors of monoamine oxidase

Cited by 2 publications

References 34 publications

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

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

Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

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