Bromophenols from Symphyocladia latiuscula Target Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Progressive degeneration of dopaminergic neurons in the substantia nigra is the characteristic feature of Parkinson's disease (PD) and the severity accelerates with aging. Therefore, improving dopamine level or dopamine receptor signaling is a standard approach for PD treatment. Herein, our results demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) from red alga Symphyocladia latiuscula are moderate-selective human monoamine oxidase-A inhibitors and good dopamine D₃/D₄ receptor agonists. Bromophenol 3 showed a promising D₄R agonist effect with a low micromole 50% effective concentration (EC₅₀) value. All of the test ligands were docked against a three-dimensional (3D) model of hD₃R and hD₄R, and the result demonstrated strong binding through interaction with prime interacting residues - Asp110, Cys114, and His349 on hD₃R and Asp115 and Cys119 on hD₄R. Overall, the results demonstrated natural bromophenols, especially 1 and 3, from Symphyocladia latiuscula as multitarget ligands for neuroprotection, especially in PD and schizophrenia.