Elkamhawy, Ahmed Woo, Jiyu Gouda, Noha A. Kim, Jushin Nada, Hossam Roh, Eun Joo Park, Ki Duk Cho, Jungsook Lee, Kyeong 2024-01-19T13:33:39Z 2024-01-19T13:33:39Z 2022-01-10 2021-10 2076-3921 https://pubs.kist.re.kr/handle/201004/116316 Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson&apos;s disease (PD). Herein, 24 melatonin analogues (3a-x) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells. Structure elucidation, characterization, and purity of the synthesized compounds were performed using H-1-NMR, C-13-NMR, HRMS, and HPLC. At 10 mu M, 12 compounds showed > 50% MAO-B inhibition. Among them, compounds 3n, 3r, and 3u-w showed > 70% inhibition of MAO-B and IC50 values of 1.41, 0.91, 1.20, 0.66, and 2.41 mu M, respectively. When compared with the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 3n, 3r, 3u, and 3v demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds 3n and 3r exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress. Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response. Taken together, these data show that compounds 3n and 3r could be further exploited for their multi-targeted role in oxidative stress-related PD therapy.</p> English MDPI MONOAMINE-OXIDASE-B MITOCHONDRIAL COMPLEX-I PARKINSONS-DISEASE HEME OXYGENASE-1 GROWTH-FACTOR DERIVATIVES ANTIOXIDANT DISCOVERY SAFINAMIDE DESIGN Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress Article 10.3390/antiox10101604 1 ANTIOXIDANTS, v.10, no.10 ANTIOXIDANTS 10 10 scie scopus 000716278200001 2-s2.0-85116826066 Biochemistry & Molecular Biology Chemistry, Medicinal Food Science & Technology Biochemistry & Molecular Biology Pharmacology & Pharmacy Food Science & Technology Article MONOAMINE-OXIDASE-B MITOCHONDRIAL COMPLEX-I PARKINSONS-DISEASE HEME OXYGENASE-1 GROWTH-FACTOR DERIVATIVES ANTIOXIDANT DISCOVERY SAFINAMIDE DESIGN bioactive molecules oxidative stress neurodegeneration brain health Parkinson&apos s disease MAO-B melatonin neuroprotection in silico docking simulation PC12 cells