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Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine-
Mohamed H Elsherbeny1,2,3, Jushin Kim4,5, Noha A Gouda6
1Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
Abstract:
Monoamine oxidase B (MAO-B) is responsible for dopamine metabolism and plays a key role in oxidative stress by changing the redox state of neuronal and glial cells. To date, no disease-modifying therapy for Parkinson's disease (PD) has been identified. However, MAO-B inhibitors have emerged as a viable therapeutic strategy for PD patients. Herein, a novel series of indole-based small molecules was synthesized as new MAO-B inhibitors with the potential to counteract the induced oxidative stress in PC12 cells. At a single dose concentration of 10 µM, 10 compounds out of 30 were able to inhibit MAO-B with more than 50%. Among them, compounds 7b, 8a, 8b, and 8e showed 84.1, 99.3, 99.4, and 89.6% inhibition over MAO-B and IC50 values of 0.33, 0.02, 0.03, and 0.45 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 7b, 8a, 8b and 8e showed remarkable selectivity indices (SI > 305, 3649, 3278, and 220, respectively). A further kinetic study displayed a competitive mode of action for 8a and 8b over MAO-B with Ki values of 10.34 and 6.63 nM. Molecular docking studies of the enzyme-inhibitor binding complexes in MAO-B revealed that free NH and substituted indole derivatives share a common favorable binding mode: H-bonding with a crucial water "anchor" and Tyr326. Whereas in MAO-A the compounds failed to form favorable interactions, which explained their high selectivity. In addition, compounds 7b, 8a, 8b, and 8e exhibited safe neurotoxicity profiles in PC12 cells and partially reversed 6-hydroxydopamine- and rotenone-induced cell death. Accordingly, we report compounds 7b, 8a, 8b, and 8e as novel promising leads that could be further exploited for their multi-targeted role in the development of a new oxidative stress-related PD therapy.
Insights
Novel indole-based compounds show potent and selective inhibition of monoamine oxidase B (MAO-B), offering a promising therapeutic strategy for Parkinson's disease (PD) by counteracting oxidative stress.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- Monoamine oxidase B (MAO-B) is crucial in dopamine metabolism and oxidative stress, implicated in Parkinson's disease (PD) pathogenesis.
- Currently, no disease-modifying therapies exist for PD, highlighting the need for novel therapeutic strategies targeting MAO-B.
- MAO-B inhibitors represent a viable approach for PD treatment, aiming to mitigate associated oxidative stress.
Purpose of the Study:
- To synthesize and evaluate a novel series of indole-based small molecules as potential MAO-B inhibitors.
- To assess the compounds' ability to counteract oxidative stress in neuronal and glial cells.
- To investigate the selectivity and mechanism of action of the most potent inhibitors.
Main Methods:
- Synthesis of 30 indole-based small molecules.
- In vitro MAO-B inhibition assays to determine IC50 values and selectivity indices (SI) against MAO-A.
- Kinetic studies to elucidate the mode of enzyme inhibition.
- Molecular docking simulations to predict binding interactions within MAO-B and MAO-A.
- Neurotoxicity assessments in PC12 cells and evaluation of protective effects against 6-hydroxydopamine and rotenone-induced cell death.
Main Results:
- Ten out of 30 synthesized compounds inhibited MAO-B by over 50% at 10 µM.
- Compounds 7b, 8a, 8b, and 8e demonstrated potent MAO-B inhibition (84.1–99.4%) with low IC50 values (0.02–0.45 µM).
- These compounds exhibited remarkable selectivity for MAO-B over MAO-A (SI > 220), significantly exceeding that of rasagiline.
- Compounds 8a and 8b displayed competitive inhibition kinetics with nanomolar Ki values.
- Molecular docking revealed favorable binding interactions of these compounds within the MAO-B active site.
- The compounds showed safe neurotoxicity profiles and partially protected PC12 cells from oxidative stress-induced death.
Conclusions:
- Compounds 7b, 8a, 8b, and 8e are identified as potent and selective MAO-B inhibitors.
- These novel indole derivatives hold promise as multi-targeted agents for Parkinson's disease therapy, addressing both MAO-B inhibition and oxidative stress.
- Further investigation is warranted to explore their therapeutic potential in preclinical PD models.
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