Novel Insights on Benzo[b]thiophene Analogues for MAO-B Inhibition and Neuroprotection: Design, Synthesis, Molecular Modelling Studies and Biological Activity

Neurodegenerative disorders (NDs), such as Alzheimer’s disease and Parkinson’s disease (PD), represent a significant challenge for ageing populations, with their prevalence increasing worldwide. Elevated human Monoamine Oxidase B (hMAO-B) activity has been related to neurodegenerative progression, where it contributes, among others, to oxidative stress and neuroinflammation. The identification and optimization of selective hMAO-B inhibitors is therefore pivotal in addressing the progression of NDs. In this work we introduced 2-aroylbenzothiophene analogues as promising agents to mitigate neurodegeneration. The synthesized compounds were screened against hMAO-A and hMAO-B, identifying compounds 4, 11, and 12 as the most promising. In vitro studies in hGF and SH-SY5Y cells revealed distinct toxicity profiles, with compound 4 being the least tolerated at 100 µM. ROS generation was investigated as a possible mechanism underlying this toxicity. Compounds 4 (12.5 µM), 11, and 12 (100 µM) were further evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced toxicity in SH-SY5Y cells, showing a modest neuroprotective effect after 72 h at a sub-toxic 6-OHDA concentration (250 µM), comparable to the clinically used hMAO-B inhibitor (R)-(−)-Deprenyl at 100 µM. Finally, molecular modelling studies revealed that compound 4 establishes key stabilizing interactions within hMAO-B, accounting for its high inhibitory potency and selectivity over hMAO-A.