Novel Insights on Benzo[b]thiophene Analogues for MAO-B Inhibition and Neuroprotection: Design, Synthesis, Molecular Modelling Studies and Biological Activity.
The paper describes synthesis, in vitro screening, and molecular modeling of 2‑aroylbenzothiophene analogues that are selective hMAO‑B inhibitors (notably compounds 4, 11, 12) and show modest neuroprotection in SH‑SY5Y cells versus 6‑OHDA, but exhibit cytotoxicity/ROS generation at high micromolar…
What the AI sees
The paper describes synthesis, in vitro screening, and molecular modeling of 2‑aroylbenzothiophene analogues that are selective hMAO‑B inhibitors (notably compounds 4, 11, 12) and show modest neuroprotection in SH‑SY5Y cells versus 6‑OHDA, but exhibit cytotoxicity/ROS generation at high micromolar…
Research significance
Provides a novel chemotype and structural insights for selective MAO‑B inhibition—a validated Parkinson's target—offering a lead series for medicinal chemistry optimization toward neuroprotective agents, though potency, toxicity and in vivo validation remain unresolved.
Source abstract
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.