Elsherbeny, M.H. Kim, J. Gouda, N.A. Gotina, L. Cho, J. Pae, A.N. Lee, K. Park, K.D. Elkamhawy, A. Roh, E.J. 2024-01-19T13:33:25Z 2024-01-19T13:33:25Z 2022-01-10 2021-10 2076-3921 https://pubs.kist.re.kr/handle/201004/116301 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 ？M, 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 ？M, 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. ？ 2021 by the authors. Licensee MDPI, Basel, Switzerland. English MDPI Highly potent, selective, and competitive indole-based MAO-B inhibitors protect PC12 cells against 6-hydroxydopamine-and rotenone-induced oxidative stress Article 10.3390/antiox10101641 1 Antioxidants, v.10, no.10 Antioxidants 10 10 N scie scopus 000716119700001 2-s2.0-85117340732 Biochemistry & Molecular Biology Chemistry, Medicinal Food Science & Technology Biochemistry & Molecular Biology Pharmacology & Pharmacy Food Science & Technology Article PARKINSONS-DISEASE IN-VITRO DISCOVERY SAFINAMIDE SCAFFOLD GENDER 6-hydroxydopamine Competitive inhibitors MAO-B inhibitors Monoamine oxidase B Oxidative stress Parkinson’s disease PC12 cells Rotenone