{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:41:09Z","timestamp":1788381669696,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003693","name":"Korea Institute of Science and Technology","doi-asserted-by":"publisher","award":["2E31140"],"award-info":[{"award-number":["2E31140"]}],"id":[{"id":"10.13039\/501100003693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2018R1A5A2023127"],"award-info":[{"award-number":["NRF-2018R1A5A2023127"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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\u2019s 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 \u00b5M, 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 \u00b5M, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI &gt; 50), compounds 7b, 8a, 8b and 8e showed remarkable selectivity indices (SI &gt; 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 \u201canchor\u201d 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.<\/jats:p>","DOI":"10.3390\/antiox10101641","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T01:23:46Z","timestamp":1634693026000},"page":"1641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3943-9585","authenticated-orcid":false,"given":"Mohamed H.","family":"Elsherbeny","sequence":"first","affiliation":[{"name":"Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea"},{"name":"Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea"},{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jushin","family":"Kim","sequence":"additional","affiliation":[{"name":"Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea"},{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha A.","family":"Gouda","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5262-9746","authenticated-orcid":false,"given":"Lizaveta","family":"Gotina","sequence":"additional","affiliation":[{"name":"Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea"},{"name":"Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsook","family":"Cho","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ae Nim","family":"Pae","sequence":"additional","affiliation":[{"name":"Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea"},{"name":"Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7753-214X","authenticated-orcid":false,"given":"Ki Duk","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea"},{"name":"Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7398-6155","authenticated-orcid":false,"given":"Ahmed","family":"Elkamhawy","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Joo","family":"Roh","sequence":"additional","affiliation":[{"name":"Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea"},{"name":"Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Harris, J.R. 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