Discovery of Carbazole and Theophylline-Based Amyloid Inhibitor for the Promotion of Neuroprotection

The amyloid-beta 42 (Aß42) peptide assembles into neurotoxic soluble oligomers and extracellular fibrillary aggregates during the progression of Alzheimer’s disease (AD), which ultimately leads to amyloid plaque in the brain, causing major disruption of the neural circuit and leading to the severe loss of memory. Thus, perturbation or inhibition of this process through the development of advanced inhibitors is crucial for the treatment of AD. Here, we adopted an advanced strategy that showcases the design of a carbazole-based chemical inhibitor targeting the Aß peptide. The new inhibitors are designed in such a way that they can bind selectively with the Aß42 peptide and inhibit the assembly process and disease progression. Initial assessments using the thioflavin-T assay and molecular docking experiments help screen the carbazole and theophylline-based CT-01 as effective lead molecules, which bind at the N-terminal hydrophobic region of the Aß42 peptide and inhibit the formation of soluble oligomers and extracellular fibrillary aggregates. Further, FT-IR spectroscopy, CD, TEM, dot blot, and ITC experiments suggest the inhibition potency of CT-01. Finally, the neuroprotection and apoptosis assay confirm that CT-01 reduces amyloid-mediated toxicity in neurons. The serum-stable CT-01 can also protect the NGF-deprived neurons and has the ability to cross the blood-brain barrier. © 2025 American Chemical Society.