Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress

• Published in: Antioxidants Vol. 10; no. 10; p. 1641
• Main Authors: Elsherbeny, Mohamed H, Kim, Jushin, Gouda, Noha A, Gotina, Lizaveta, Cho, Jungsook, Pae, Ae Nim, Lee, Kyeong, Park, Ki Duk, Elkamhawy, Ahmed, Roh, Eun Joo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.10.2021; MDPI
• Subjects: 6-Hydroxydopamine; Alzheimer's disease; Amine oxidase (flavin-containing); Cell death; Chromatography; competitive inhibitors; Glial cells; Indoles; MAO-B inhibitors; Metabolism; monoamine oxidase B; Movement disorders; Neurodegenerative diseases; Neuronal-glial interactions; Neurotoxicity; Oxidative stress; Parkinson's disease; Pheochromocytoma cells; Rasagiline; Redox properties; Rotenone; 6-hydroxydopamine; MAO-B inhibitors; rotenone; monoamine oxidase B; PC12 cells; Parkinson’s disease; oxidative stress; competitive inhibitors
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox10101641

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 , , , and showed 84.1, 99.3, 99.4, and 89.6% inhibition over MAO-B and IC values of 0.33, 0.02, 0.03, and 0.45 µM, respectively. When compared to the modest selectivity index of rasagiline ( , a well-known MAO-B inhibitor, SI > 50), compounds , , and showed remarkable selectivity indices (SI > 305, 3649, 3278, and 220, respectively). A further kinetic study displayed a competitive mode of action for and over MAO-B with i 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 , , , and exhibited safe neurotoxicity profiles in PC12 cells and partially reversed 6-hydroxydopamine- and rotenone-induced cell death. Accordingly, we report compounds , , , and 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.