| Summary: | 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’s disease (PD). Herein, 24 melatonin analogues (<b>3a</b>–<b>x</b>) 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 <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds <b>3n</b>, <b>3r</b>, and <b>3u</b>–<b>w</b> showed >70% inhibition of MAO-B and IC<sub>50</sub> values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively. When compared with the modest selectivity index of rasagiline (<b>II</b>, a well-known MAO-B inhibitor, SI > 50), compounds <b>3n, 3r, 3u</b>, and <b>3v</b> demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds <b>3n</b> and <b>3r</b> 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 <b>3n</b> and <b>3r</b> could be further exploited for their multi-targeted role in oxidative stress-related PD therapy.
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